Active ingredients: Vildagliptin
Galvus 50 mg tablets
Indications Why is Galvus used? What is it for?
The active substance in Galvus, vildagliptin, belongs to a group of medicines called 'oral antidiabetics'.
Galvus is used to treat adult patients with type 2 diabetes. It is used when diabetes cannot be controlled by diet and exercise alone. It helps to control the level of sugar in the blood. Your doctor will prescribe Galvus alone or together. other antidiabetic medicines you are already taking, if these have not been shown to be effective enough to control diabetes.
Type 2 diabetes develops when the body does not make enough insulin, or if the insulin the body produces does not work as it should. It can also develop when the body produces too much glucagon.
Insulin is a substance that helps lower blood sugar levels, especially after meals. Glucagon is a substance that triggers the production of sugar by the liver, causing blood sugar levels to rise. The pancreas produces both of these substances.
How Galvus works
Galvus works by causing the pancreas to produce more insulin and less glucagon. This helps to control the blood sugar level. This medicine has been shown to reduce blood sugar. This can help prevent complications from your diabetes. Even if you start taking diabetes medicine now, it is important that you continue to follow the recommended diet and / or exercise.
Contraindications When Galvus should not be used
Do not take Galvus:
- if you are allergic to vildagliptin or any of the other ingredients of this medicine (listed in section 6). If you think you may be allergic to vildagliptin or any of the other ingredients of Galvus, do not take this medicine and contact your doctor.
Precautions for use What you need to know before taking Galvus
Talk to your doctor, pharmacist or diabetes nurse before taking Galvus
- if you have type 1 diabetes (your body does not make insulin) or if you have a condition called diabetic ketoacidosis.
- if you are taking an anti-diabetic medicine known as a sulphonylurea (if you take it together with Galvus, your doctor may want to reduce your sulphonylurea dose to avoid low blood glucose [hypoglycaemia]).
- if you have moderate or severe kidney disease (you will need to take a lower dose of Galvus).
- if you are on dialysis
- if you have liver disease
- if you suffer from heart failure
- if you have or have ever had pancreatic disease
If you have previously taken vildagliptin but had to stop due to liver disease, you should not take this medicine.
Skin lesions are a common complication of diabetes. It is advisable to follow the recommendations for skin and foot care given to you by your doctor or nurse. You should also pay particular attention to the development of blisters or ulcers while taking Galvus. If this occurs you should consult your doctor quickly.
Before starting treatment with Galvus, an examination will be carried out to evaluate the functioning of the liver, which will be repeated every three months during the first year of treatment and periodically thereafter. This is to detect signs of increased liver enzymes as soon as possible.
Children and adolescents
The use of Galvus in children and adolescents up to 18 years of age is not recommended.
Interactions Which drugs or foods can modify the effect of Galvus
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Your doctor may want to change the dose of Galvus if you are taking other medicines such as:
- thiazides or other diuretics (also called urinating tablets) - corticosteroids (usually used to treat inflammation)
- thyroid medicines
- certain medicines that affect the nervous system.
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 must not use Galvus during pregnancy. It is not known if Galvus passes into breast milk. You should not use Galvus if you are breastfeeding or plan to breastfeed.
Driving and using machines
If you feel dizzy when taking Galvus, do not drive or use machines.
Galvus contains lactose
Galvus contains lactose (milk sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Galvus: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
How much to take and when
The amount of Galvus that must be taken varies according to individual conditions. Your doctor will tell you exactly how many Galvus tablets to take. The maximum daily dose is 100 mg.
The usual dose of Galvus is:
- 50 mg per day taken as a single dose in the morning if you take Galvus with another medicine called sulfonylurea.
- 100 mg per day taken as 50 mg in the morning and 50 mg in the evening if you take Galvus alone, with another medicine called metformin or a glitazone, with a combination of metformin and a sulphonylurea, or with insulin.
- 50 mg daily in the morning if you have moderate or severe kidney disease or are on dialysis.
How to take Galvus
- Swallow the tablets with some water.
How long to take Galvus
- Take Galvus every day for as long as your doctor recommends. You may need to continue this treatment for a long time.
- Your doctor will check your condition regularly to make sure that the treatment is having the desired effect.
If you forget to take Galvus
If you forget to take a dose of this medicine, take it as soon as you remember. Then take the next dose at the usual time. 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 tablet.
If you stop taking Galvus
Do not stop taking Galvus unless your doctor tells you to. If you are unsure how long you will be taking this medicine, ask your doctor.
Overdose What to do if you have taken too much Galvus
If you take too many Galvus tablets, or if someone else has taken your medicine, contact your doctor immediately. Medical attention may be required. If you need to see a doctor or go to the hospital, take the pack with you.
Side Effects What are the side effects of Galvus
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Some symptoms require immediate medical attention:
You must stop taking Galvus and contact your doctor immediately if any of the following side effects occur:
- Angioedema (rare: may affect up to 1 in 1,000 people): Symptoms include swelling of the face, tongue or throat, difficulty swallowing, difficulty breathing, sudden rash or hives, which may indicate a reaction called " angioedema ".
- Liver disease (hepatitis) (rare): Symptoms include yellow skin and eyes, nausea, loss of appetite, or dark colored urine, which may indicate liver disease (hepatitis).
- Inflammation of the pancreas (pancreatitis) (frequency not known). Symptoms include severe and persistent pain in the abdomen (stomach area) which may extend to the back, as well as nausea and vomiting.
Other side effects
Some patients have experienced the following side effects while taking Galvus and metformin:
- Common (may affect up to 1 in 10 people): tremor, headache, dizziness, nausea, low blood glucose levels.
- Uncommon (may affect up to 1 in 100 people): tiredness.
Some patients have experienced the following side effects while taking Galvus and a sulphonylurea:
- Common: tremor, headache, dizziness, weakness, low blood glucose levels.
- Uncommon: constipation.
- Very rare (may affect up to 1 in 10,000 people): sore throat, runny nose.
Some patients have experienced the following side effects while taking Galvus and a glitazone:
- Common: weight gain, swelling of the hands, ankles or feet (edema).
- Uncommon: headache, weakness, low blood glucose levels.
Some patients have experienced the following side effects while taking Galvus alone:
- Common: dizziness.
- Uncommon: headache, constipation, swelling of the hands, ankles or feet (edema), pain in the joints, low blood glucose levels.
- Very rare: sore throat, runny nose, fever.
Some patients have experienced the following side effects while taking Galvus, metformin and a sulphonylurea:
- Common: dizziness, tremor, weakness, low blood glucose, excessive sweating.
Some patients have experienced the following side effects while taking Galvus and insulin (with or without metformin):
- Common: headache, chills, nausea (feeling sick), low blood glucose levels, heartburn.
- Uncommon: diarrhea, flatulence.
The following side effects have also been reported during the marketing of this medicine:
- Frequency not known (cannot be estimated from the available data): itchy rash, inflammation of the pancreas, localized peeling of the skin or blisters, muscle pain.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or diabetes 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. By reporting 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" / "EXP". The expiry date refers to the last day of that month.
- Store in the original package to protect from moisture.
- Do not use a Galvus pack that is damaged or shows signs of tampering.
Expiry "> Other interactions
What Galvus contains
- The active ingredient is vildagliptin. Each tablet contains 50 mg of vildagliptin.
- The other ingredients are anhydrous lactose, microcrystalline cellulose, sodium starch glycolate (type A) and magnesium stearate.
Description of what Galvus looks like and contents of the pack
Galvus 50 mg tablets are round, flat, white to slightly yellowish, with "NVR" on one side and "FB" on the other.
Galvus 50 mg tablets are available in packs containing 7, 14, 28, 30, 56, 60, 90, 112, 180 or 336 tablets and in multipacks containing 3 cartons, each containing 112 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 -
GALVUS 50 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Each tablet contains 50 mg of vildagliptin.
Excipient with known effect: each tablet contains 47.82 mg of lactose (anhydrous).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Tablet.
Round (8 mm diameter), white to slightly yellowish, flat tablet with beveled edges.
The letters "NVR" are embossed on one side, "FB" on the other.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
Vildagliptin is indicated for the treatment of type 2 diabetes mellitus in adults:
In monotherapy
- in patients inadequately controlled by diet and exercise alone and for whom metformin therapy is inappropriate due to contraindications or intolerance.
In dual oral therapy in association with:
- metformin, in patients with insufficient glycemic control despite the administration of the maximum tolerated dose of metformin alone,
- a sulfonylurea, in patients with insufficient glycemic control despite the administration of the maximum tolerated dose of a sulphonylurea and for whom metformin therapy is inappropriate due to contraindications or intolerance,
- a thiazolidinedione, in patients with insufficient glycemic control and for whom the use of a thiazolidinedione is appropriate.
In triple oral therapy in combination with:
- a sulphonylurea and metformin when diet and exercise associated with dual therapy with these drugs do not provide adequate glycemic control.
Vildagliptin is also indicated for use in combination with insulin (with or without metformin) when diet and exercise combined with a stable dose of insulin do not provide adequate glycemic control.
04.2 Posology and method of administration -
Dosage
Adults
When used alone, in combination with metformin, in combination with a thiazolidinedione, in combination with metformin and a sulphonylurea, or in combination with insulin (with or without metformin), the recommended daily dose of vildagliptin is 100 mg, given in one dose. 50 mg in the morning and a 50 mg dose in the evening.
When used in dual therapy in combination with a sulphonylurea, the recommended dose of vildagliptin is 50 mg once daily, administered in the morning. In this patient population, vildagliptin 100 mg daily was no more effective than vildagliptin 50 mg once daily.
When used in combination with a sulfonylurea, a lower dose of sulfonylurea may be considered to reduce the risk of hypoglycaemia.
Doses above 100 mg are not recommended.
If a dose of Galvus is missed, it should be taken as soon as the patient remembers it.
A double dose should not be taken on the same day.
The safety and efficacy of vildagliptin as oral triple therapy in combination with metformin and a thiazolidinedione have not been established.
Additional information for particular patient populations
Elderly (≥ 65 years old)
No dose adjustment is necessary in elderly patients (see also sections 5.1 and 5.2).
Impaired renal function
No dose adjustment is required in patients with mildly impaired renal function (clearance creatinine ≥ 50 ml / min). In patients with moderate or severe renal impairment or end stage renal disease (ESRD), the recommended dose of Galvus is 50 mg once daily (see also sections 4.4, 5.1 and 5.2).
Impaired liver function
Galvus should not be used in patients with hepatic impairment, including patients who have alanine aminotransferase (ALT) or aspartate aminotransferase (AST)> 3x upper limit of normal (ULN) before treatment (see also sections 4.4 and 5.2).
Pediatric population
The use of Galvus is not recommended in children and adolescents (
Method of administration
Oral use
Galvus can be taken with or without food (see also section 5.2).
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
Galvus is not a substitute for insulin in insulin-dependent patients. Galvus should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Impaired renal function
Experience in hemodialysis patients with ESRD is limited. Therefore Galvus should be used with caution in these patients (see also sections 4.2, 5.1 and 5.2).
Impaired liver function
Galvus should not be used in patients with hepatic impairment, including patients with pre-treatment ALT or AST> 3x ULN (see also sections 4.2 and 5.2).
Monitoring of liver enzymes
Rare cases of hepatic dysfunction (including hepatitis) have been reported. In these cases, patients were generally asymptomatic with no clinical consequences and liver function tests returned to normal after discontinuation of treatment. Liver function tests should be performed before starting treatment with Galvus to know the patient's baseline value. During treatment with Galvus, liver function should be checked every three months during the first year of treatment and periodically thereafter. Patients who develop elevated transaminase levels should be checked with a second liver function assessment to confirm the results and then followed up with frequent liver function tests until the abnormality (s) returns to normal. . If the elevation of AST or ALT persists at 3 times the upper limit of normal or above, it is recommended that Galvus therapy be discontinued. Patients who develop jaundice or other signs suggesting hepatic dysfunction should discontinue Galvus treatment. .
After discontinuation of Galvus treatment and normalization of liver function parameters, Galvus treatment should not be restarted.
Heart failure
A clinical study of vildagliptin in patients in New York Heart Association (NYHA) functional classes I-III showed that vildagliptin treatment was not associated with changes in left ventricular function or worsening of pre-existing congestive heart failure (CHF) compared to placebo. Clinical experience in NYHA functional class III patients treated with vildagliptin is still limited and the results are inconclusive (see section 5.1).
There is no experience with the use of vildagliptin in clinical trials in patients with NYHA functional class IV and therefore its use is not recommended in these patients.
Skin disorders
In non-clinical toxicology studies, skin lesions, including blisters and ulcerations, have been reported on the extremities of monkeys (see section 5.3). Although an "increased incidence of skin lesions" was not observed in clinical trials, there was limited experience in patients with diabetic skin complications. In addition, there have been post-marketing reports of bullous and exfoliative skin lesions. In accordance with the routine care of the diabetic patient, monitoring of any skin diseases, such as blisters and ulcerations, is therefore recommended.
Acute pancreatitis
The use of vildagliptin has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis.
If pancreatitis is suspected, vildagliptin should be discontinued; if acute pancreatitis is confirmed, vildagliptin should not be restarted. Caution should be exercised in patients with a history of acute pancreatitis.
Hypoglycemia
Sulfonylureas are known to cause hypoglycemia. Patients receiving vildagliptin in combination with a sulphonylurea may be at risk for hypoglycaemia. Therefore, a lower dose of sulphonylurea may be considered to reduce the risk of hypoglycaemia.
Excipients
The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction -
Vildagliptin has a low potential for interaction when combined with other medicinal products. Since vildagliptin is not a substrate of the cytochrome P (CYP) 450 enzyme and does not inhibit or induce CYP 450 enzymes, interaction with active substances that are substrates, inhibitors or inducers of these enzymes is not likely.
Combination with pioglitazone, metformin and glibenclamide
The results of studies conducted with these oral antidiabetics did not reveal clinically relevant pharmacokinetic interactions.
Digoxin (substrate of p-glycoprotein), warfarin (substrate of CYP2C9)
Clinical studies conducted with healthy subjects did not reveal clinically relevant pharmacokinetic interactions. However, this evidence was not confirmed in the reference population.
Combination with amlodipine, ramipril, valsartan or simvastatin
Drug-drug interaction studies were conducted with amlodipine, ramipril, valsartan and simvastatin in healthy subjects. In these studies, no clinically relevant pharmacokinetic interactions were observed following co-administration with vildagliptin.
As with other oral antidiabetics, the hypoglycaemic effect of vildagliptin may be reduced by some active substances, including thiazides, corticosteroids, thyroid medicines and sympathomimetics.
04.6 Pregnancy and breastfeeding -
Pregnancy
There are no adequate data from the use of vildagliptin 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, Galvus should not be used during pregnancy.
Feeding time
It is unknown whether vildagliptin is excreted in human milk. Animal studies have shown excretion of vildagliptin in milk. Galvus should not be used during lactation.
Fertility
No studies on the effect of Galvus on human fertility have been conducted (see section 5.3).
04.7 Effects on ability to drive and use machines -
No studies on the ability to drive and use machines have been performed. Patients who experience dizziness as an adverse reaction should avoid driving or using machines.
04.8 Undesirable effects -
Summary of the safety profile
Safety data were obtained from a total of 3,784 patients exposed to daily doses of vildagliptin of 50 mg (once daily) or 100 mg (50 mg twice daily or 100 mg once daily) in controlled studies. lasting at least 12 weeks. Of these patients, 2,264 received vildagliptin alone and 1,520 received vildagliptin in combination with another medicine. 2,682 patients were treated with vildagliptin 100 mg daily (50 mg twice daily or 100 mg once daily) and 1,102 patients were treated with vildagliptin 50 mg once daily.
Most adverse reactions in these clinical trials were mild and transient in nature and did not require discontinuation of therapy. There was no association between adverse reactions and age, ethnicity, duration of exposure. or the daily dose.
Rare cases of hepatic dysfunction (including hepatitis) have been reported. In these cases, patients were generally asymptomatic with no clinical consequences and liver function tests returned to normal after discontinuation of treatment. From data from controlled monotherapy or add-on therapy studies of up to 24 weeks duration, the incidence of ALT or AST elevations ≥ 3 times the upper limit of normal (classified as present in at least 2 consecutive controls or at final visit during treatment) was 0.2%, 0.3% and 0.2% for vildagliptin 50 mg once daily, vildagliptin 50 mg twice daily and all comparators, respectively. These transaminase elevations were generally asymptomatic, non-progressive in nature and not associated with cholestasis or jaundice.
Rare cases of angioedema have been reported with vildagliptin, with an incidence similar to the control group. The majority of cases were reported when vildagliptin was administered in combination with an angiotensin enzyme inhibitor (ACE inhibitor). Most events were of moderate severity and resolved during treatment with vildagliptin.
Table of adverse reactions
Adverse reactions reported in patients who received Galvus in double-blind studies as monotherapy and add-on therapy are listed below for each indication by system organ class and absolute frequency. Frequencies are defined as very common (≥1 / 10), common (≥1 / 100,
Combination with metformin
Table 1 Adverse reactions reported in patients who received Galvus 100 mg daily in add-on combination with metformin in double-blind studies (N = 208)
Description of selected adverse reactions
In controlled clinical trials performed with the combination of vildagliptin 100 mg daily + metformin, no withdrawals due to adverse reactions were reported in either the vildagliptin 100 mg daily + metformin group or the placebo + metformin group. In clinical studies, the incidence of hypoglycaemia was common in patients who received vildagliptin 100 mg daily in combination with metformin (1%) and uncommon in patients who received placebo + metformin (0.4%). No serious hypoglycaemic events were reported in the vildagliptin arms.
In clinical studies, weight did not change from baseline when vildagliptin 100 mg daily was added to metformin (+0.2 kg and -1.0 kg for vildagliptin and placebo, respectively).
Clinical studies of up to more than 2 years duration have shown no additional safety signals or unanticipated risks when vildagliptin was combined with metformin.
Combination with a sulfonylurea
Table 2 Adverse reactions reported in patients who received Galvus 50 mg in combination with a sulfonylurea in double-blind studies (N = 170)
Description of selected adverse reactions
In controlled clinical trials performed with the combination vildagliptin 50 mg + a sulfonylurea, the overall incidence of withdrawals due to adverse reactions was 0.6% in the vildagliptin 50 mg + sulfonylurea group versus 0% in the group treated with placebo + sulfonylurea.
In clinical studies, when vildagliptin 50 mg once daily was added to glimepiride the incidence of hypoglycaemia was 1.2% versus 0.6% with placebo + glimepiride. No serious hypoglycaemic events were reported in the arms with vildagliptin.
In clinical studies, weight did not change from baseline when vildagliptin 50 mg daily was added to glimepiride (-0.1 kg and -0.4 kg for vildagliptin and placebo, respectively).
Association with a thiazolidinedione
Table 3 Adverse reactions reported in patients who received Galvus 100 mg daily in combination with a thiazolidinedione in double-blind studies (N = 158)
Description of selected adverse reactions
In controlled clinical trials performed with the combination vildagliptin 100 mg daily + a thiazolidinedione, in both the vildagliptin 100 mg daily + thiazolidinedione and placebo + thiazolidinedione groups, no withdrawals were reported due to adverse reactions. In clinical studies, the incidence of hypoglycaemia was uncommon in patients who received vildagliptin + pioglitazone (0.6%) while it was common in patients who received placebo + pioglitazone (1.9%). No serious hypoglycaemic events were reported in the vildagliptin arms. In the add-on studies with pioglitazone, the absolute weight gains with placebo and Galvus 100 mg daily were 1.4 and 2.7 kg, respectively.
The incidence of peripheral edema when vildagliptin 100 mg daily was added to background therapy with pioglitazone at the maximum dose (45 mg once daily) was 7.0%, compared with 2.5% for pioglitazone alone. .
Monotherapy
Table 4 Adverse reactions reported in patients who received Galvus 100 mg daily as monotherapy in double-blind studies (N = 1,855)
Description of selected adverse reactions
In addition, in controlled clinical trials performed with vildagliptin administered alone the overall incidence of withdrawals due to adverse reactions was not higher for patients treated with vildagliptin at 100 mg daily (0.3%) compared to patients treated with placebo (0.6%) or comparator (0.5%).
In comparative controlled monotherapy studies, hypoglycaemia was uncommon and was reported in 0.4% (7 of 1,855) of patients treated with vildagliptin at 100 mg daily compared with 0.2% (2 of 1,082 ) of patients in the active comparator or placebo groups, with no serious or serious events reported.
In clinical studies, weight did not change from baseline when vildagliptin 100 mg daily was administered as monotherapy (-0.3 kg and -1.3 kg for vildagliptin and placebo, respectively). showed no additional safety signals or unexpected risks with vildagliptin alone.
Combination with metformin and a sulphonylurea
Table 5 Adverse reactions reported in patients who received Galvus 50 mg twice daily in combination with metformin and a sulphonylurea (N = 157)
Description of selected adverse reactions
There were no withdrawals due to adverse reactions reported in the vildagliptin + metformin + glimepiride treatment group compared to 0.6% in the placebo + metformin + glimepiride treatment group.
The incidence of hypoglycaemia was common in both treatment groups (5.1% for the vildagliptin + metformin + glimepiride group versus 1.9% for the placebo + metformin + glimepiride group).
One severe hypoglycemic event was reported in the vildagliptin group.
At the end of the study, the effect on mean body weight was neutral (+0.6 kg in the vildagliptin group and -0.1 kg in the placebo group).
Association with insulin
Table 6 Adverse reactions reported in patients who received Galvus 100 mg daily in combination with insulin (with or without metformin) in double-blind studies (N = 371)
Description of selected adverse reactions
In controlled clinical trials with the combination of vildagliptin 50 mg twice daily plus insulin, with or without concomitant metformin, the overall incidence of withdrawals due to adverse reactions was 0.3% in the vildagliptin treatment group. and there were no withdrawals in the placebo group.
The incidence of hypoglycaemia was similar in both treatment groups (14.0% in the vildagliptin group versus 16.4% in the placebo group). Two patients in the vildagliptin group and 6 patients in the placebo group experienced serious hypoglycaemic events.
At the end of the study, the effect on mean body weight was neutral (+0.6 kg from baseline in the vildagliptin group and no weight change in the placebo group).
Post-marketing experience
Table 7 Post-marketing adverse reactions
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 -
Information on overdose with vildagliptin is limited.
Symptoms
Information on likely symptoms of overdose was derived from a dose-escalation tolerance study in healthy subjects treated with Galvus for 10 days. At 400 mg, there were three cases of muscle pain and individual cases of mild and transient paraesthesia, fever, edema and a transient increase in lipase levels. At 600 mg, one subject developed edema in the feet and hands and increased levels of creatine phosphokinase (CPK), aspartate aminotransferase (AST), creative protein (CRP), and myoglobin. Three other subjects developed foot edema, with paresthesia in two cases. All symptoms and laboratory abnormalities resolved without treatment after discontinuation of study drug.
Treatment
In the event of an overdose, supportive treatment is recommended. Vildagliptin cannot be eliminated by hemodialysis. However, the major hydrolysis-derived metabolite (LAY 151) can be eliminated by hemodialysis.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: Drugs used in diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC code: A10BH02
Vildagliptin belongs to the pancreatic islet modulator class of drugs and is a potent and selective inhibitor of DPP-4.
Mechanism of action
Administration of vildagliptin results in a rapid and complete inhibition of DPP-4 activity, resulting in increased endogenous fasting and postprandial levels of GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide). ).
Pharmacodynamic effects
By increasing endogenous levels of incretins, vildagliptin increases the sensitivity of beta cells to glucose, resulting in an improvement in glucose-dependent insulin secretion. Treatment with vildagliptin 50-100 mg daily in patients with type 2 diabetes significantly improved i marker beta cell function, including HOMA-b (Homeostasis Model Assessment -b), the ratio of proinsulin to insulin and measures of beta cell responsiveness in the meal tolerance test with frequent sampling. In non-diabetic subjects (normal blood glucose), vildagliptin does not stimulate insulin secretion or reduce glucose levels.
By increasing endogenous levels of GLP-1, vildagliptin also increases the sensitivity of alpha cells to glucose, resulting in adequate glucagon secretion for glucose amounts.
The increase in the insulin / glucagon ratio in hyperglycemia caused by an increase in incretin levels causes a reduction in fasting and postprandial hepatic glucose production, resulting in a reduction in blood glucose.
The known effect of increased GLP-1 levels that slow gastric emptying is not observed in vildagliptin treatment.
Clinical efficacy and safety
More than 15,000 patients with type 2 diabetes participated in double-blind placebo- or active-controlled clinical trials with a treatment duration of up to more than 2 years. In these studies, vildagliptin was administered to more than 9,000 patients at daily doses of 50 mg once daily, 50 mg twice daily or 100 mg once daily. More than 5,000 male and more than 4,000 female patients received vildagliptin 50 mg once daily or 100 mg daily. More than 1,900 patients who received vildagliptin 50 mg once daily or 100 mg daily were aged ≥ 65 years. In these studies, vildagliptin was given as monotherapy to patients with drug-naïve type 2 diabetes or in combination in patients inadequately controlled with other antidiabetic medicinal products.
Overall, vildagliptin improved glycemic control when given alone or when used in combination with metformin, a sulfonylurea and a thiazolidinedione, as reflected by clinically relevant reductions in "HbA1c from baseline at"endpoint study (see Table 8).
In clinical studies, the magnitude of HbA1c reductions with vildagliptin were greater in patients with higher baseline HbA1c values.
In a 52-week double-blind controlled study, vildagliptin (50 mg twice daily) reduced baseline HbA1c by -1% compared to -1.6% achieved with metformin (titrated to 2 g / day). Statistical non-inferiority was not obtained Patients treated with vildagliptin reported significantly lower incidences of gastrointestinal adverse reactions than those treated with metformin.
In a 24-week double-blind controlled study, vildagliptin (50 mg twice daily) was compared to rosiglitazone (8 mg once daily). In patients with mean baseline HbA1c of 8.7% the mean reductions were -1.20% with vildagliptin and -1.48% with rosiglitazone. Patients who received rosiglitazone experienced mean weight gain (+1.6 kg), while those who received vildagliptin experienced no weight gain (-0.3 kg). The incidence of peripheral edema was lower in the vildagliptin group than in the rosiglitazone group (2.1% versus 4.1%, respectively).
In a 2-year clinical study, vildagliptin (50 mg twice daily) was compared to gliclazide (up to 320 mg / day). After two years, the mean reduction in HbA1c was -0.5% for vildagliptin and -0.6% for glycazide compared to a mean baseline HbA1c of 8.6%. Statistical non-inferiority was not achieved. Vildagliptin was associated with fewer hypoglycemic events (0.7%) than glycazide (1.7%).
In a 24-week clinical study, vildagliptin (50 mg twice daily) was compared to pioglitazone (30 mg once daily) in patients inadequately controlled on metformin (mean daily dose: 2020 mg). Compared with baseline HbA1c of 8.4%, the mean reductions were -0.9% with vildagliptin in combination with metformin and -1.0% with pioglitazone in combination with metformin. In patients receiving pioglitazone in combination with metformin it is A mean weight gain of +1.9 kg was observed compared to +0.3 kg observed in those receiving vildagliptin in combination with metformin.
In a 2-year clinical study, vildagliptin (50 mg twice daily) was compared to glimepiride (up to 6 mg / day - 2-year mean dose: 4.6 mg) in patients treated with metformin (dose daily mean: 1894 mg). After 1 year, mean reductions in HbA1c were -0.4% with vildagliptin in combination with metformin and -0.5% with glimepiride in combination with metformin, compared with a mean baseline HbA1c of 7.3%. The change in body weight was -0.2 kg with vildagliptin compared to +1.6 kg with glimepiride. The incidence of hypoglycemia was significantly lower in the vildagliptin group (1.7%) than in the glimepiride group (16.2%). At the study endpoint (2 years), in both treatment groups, HbA1c was found to be similar to baseline values and body weight changes and differences in hypoglycemia were maintained.
In a 52-week study, vildagliptin (50 mg twice daily) was compared to gliclazide (mean daily dose: 229.5 mg) in patients inadequately controlled on metformin (baseline metformin dose 1928 mg / day). . After 1 year, mean reductions in HbA1c were -0.81% with vildagliptin in combination with metformin (mean baseline HbA1c 8.4%) and -0.85% with gliclazide in combination with metformin (mean baseline HbA1c 8.5%) ); statistical non-inferiority was achieved (95% CI: -0.11 - 0.20). The change in body weight was +0.1 kg with vildagliptin compared to a weight gain of +1.4 kg with gliclazide.
The efficacy of the fixed combination of vildagliptin and metformin (titrated gradually to a dose of 50 mg / 500 mg twice daily or 50 mg / 1000 mg twice daily) as therapy was evaluated in a 24-week study. initial in previously untreated patients (denovo).
HbA1c was reduced by -1.82% with vildagliptin / metformin 50 mg / 1000 mg twice daily, by -1.61% with vildagliptin / metformin 50 mg / 500 mg twice daily, by -1, 36% with metformin 1000 mg twice daily and -1.09% with vildagliptin 50 mg twice daily starting from a mean baseline HbA1c of 8.6%. ≥10.0% was more prominent.
A 24-week, double-blind, randomized, multicenter, placebo-controlled study was conducted to evaluate the treatment effect of vildagliptin 50 mg once daily versus placebo in 515 patients with type 2 diabetes and renal impairment. moderate (N = 294) or severe (N = 221). 68.8% and 80.5% of patients with moderate and severe renal impairment, respectively, had been treated with insulin (mean daily dose of 56 units and 51.6 units respectively) at baseline. In patients with moderate renal impairment, vildagliptin significantly decreased HbA1c compared to placebo (difference of -0.53%) starting from a mean baseline of 7.9%. In patients with severe renal impairment, vildagliptin has significantly decreased HbA1c compared to placebo (difference of -0.56%) starting from a mean baseline of 7.7%.
A 24-week, randomized, double-blind, placebo-controlled study was conducted in 318 patients to evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with metformin (≥1500 mg daily) and glimepiride (≥4 mg daily). Vildagliptin in combination with metformin and glimepiride significantly decreased HbA1c compared to placebo
The placebo-adjusted mean reduction in HbA1c from a mean baseline of 8.8% was -0.76%.
A 24-week, randomized, double-blind, placebo-controlled study was conducted in 449 patients to evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with a stable dose of basal or premixed insulin ( mean daily dose 41 units), with concomitant use of metformin (N = 276) or without concomitant metformin (N = 173). Vildagliptin in combination with insulin significantly decreased HbA1c compared to placebo. In the general population, the placebo-adjusted mean reduction in HbA1c from a mean baseline HbA1c of 8.8% was -0.72%. In the subgroups treated with insulin with or without concomitant metformin, the mean placebo-adjusted reduction in HbA1c was -0.63% and -0.84%, respectively. The incidence of hypoglycaemia in the general population was 8.4% and 7.2% in the vildagliptin and placebo groups, respectively. Patients receiving vildagliptin experienced no weight gain (+0.2 kg) while patients receiving placebo had manifested weight reduction (-0.7 kg).
In another 24-week study in patients with more advanced type 2 diabetes not adequately controlled on insulin (short and longer duration of action, mean insulin dose of 80 IU / day) the mean reduction in HbA1c when vildagliptin (50 mg twice daily) was added to insulin was statistically and significantly greater than with placebo + insulin (0.5% vs. 0.2%). The incidence of hypoglycemia was lower in the vildagliptin group than in the placebo group (22.9% vs. 29.6%).
A 52-week, multicenter, randomized, double-blind study was conducted in patients with type 2 diabetes and congestive heart failure (NYHA functional class I-III) to evaluate the effect of vildagliptin 50 mg twice daily (N = 128) versus placebo (N = 126) on left ventricular ejection fraction (LVEF). Vildagliptin is not associated with a change in left ventricular function or worsening of pre-existing CHF. The adjudicated cardiovascular events were overall balanced. In patients with NYHA class III heart failure treated with vildagliptin there were more cardiac events than in patients treated with placebo. However, there were biases in baseline cardiovascular risk in favor of placebo and the number of events was low, precluding definitive conclusions . Vildagliptin significantly reduced HbA1c compared to placebo (0.6% difference) from a value mean baseline of 7.8% at week 16. In the NYHA class III subgroup, the decrease in HbA1c was smaller (difference 0.3%) but this conclusion is limited due to the small number of patients (N = 44). The incidence of hypoglycaemia in the overall population was 4.7% and 5.6% in the vildagliptin and placebo groups, respectively.
Cardiovascular risk
A meta-analysis of 25 Phase III clinical trials of greater than 2 years duration of independently and prospectively awarded cardiovascular events was performed. This analysis showed that vildagliptin treatment was not associated with an increased cardiovascular risk compared to comparisons. The composite endpoint of proven cardiovascular and cerebrovascular (CCV) events [acute coronary syndrome (ACS), transient ischemic attack (with evidence of heart attack on imaging), stroke or CCV death], was similar for vildagliptin compared to the combination of comparison of active and placebo [Mantel-Haenszel risk ratio 0.84 (95% confidence interval 0.63-1.12)]. A total of 99 out of 8,956 patients in the vildagliptin group reported an event versus 91 out of 6,061 patients in the comparator group.
Table 8 Key efficacy results of vildagliptin in placebo-controlled monotherapy and add-on studies (primary efficacy in the ITT population - intention to treat)
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with vildagliptin in all subsets of the pediatric population with type 2 diabetes mellitus (see section 4.2 for information on pediatric use).
05.2 "Pharmacokinetic properties -
Absorption
Following oral administration in the fasted state, vildagliptin is rapidly absorbed, with peak plasma concentrations occurring at 1.7 hours. Food slightly delays (2.5 hours) the time to reach peak plasma concentration, but does not alter overall exposure (AUC). Administration of vildagliptin with food results in a reduced Cmax (19%). L However, the extent of the change is not clinically significant, so Galvus can be taken regardless of food. The absolute bioavailability is 85%.
Distribution
Plasma protein binding of vildagliptin is low (9.3%) and vildagliptin distributes equally between plasma and red blood cells. Following intravenous administration, the mean volume of distribution of vildagliptin allo steady state (Vss) is 71 liters, suggesting extravascular distribution.
Biotransformation
In humans, metabolism is the major elimination route for vildagliptin and accounts for 69% of the dose. The major metabolite (LAY 151) is pharmacologically inactive and is the hydrolysis product of the cyano group and accounts for 57% of the dose, followed by from glucuronide (BQS867) and amide hydrolysis products (4% of the dose). The data in vitro on human kidney microsomes suggest that the kidney may be one of the organs that contributes most to the hydrolysis of vildagliptin to its major inactive metabolite, LAY 151. DPP-4 partially contributes to the hydrolysis of vildagliptin according to a study in vivo conducted using DPP-4-free rats. Vildagliptin is not metabolised to a quantifiable extent by CYP 450 enzymes. Consequently, the metabolic clearance of vildagliptin is not expected to be affected by concomitant administration of CYP 450 inhibitor and / or inducer medicinal products. Studies in vitro demonstrated that vildagliptin does not inhibit / induce CYP 450 enzymes. Therefore vildagliptin is not likely to affect the metabolic clearance of medicinal products metabolised by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 or CYP 3A4 / 5 , when administered simultaneously.
Elimination
Following oral administration of [14C] vildagliptin, approximately 85% of the dose is excreted in the urine and 15% of the dose is recovered in the faeces. Following oral administration, renal excretion of unchanged vildagliptin amounts to 23% of the dose. In healthy subjects, following intravenous administration, the clearance total plasma and renal values of vildagliptin are 41 and 13 L / hour, respectively. After intravenous administration, the mean elimination half-life is approximately 2 hours. After oral administration, the elimination half-life is approximately 3 hours.
Linearity / Non-linearity
Within the therapeutic dose range, vildagliptin Cmax and area under the plasma concentration-time curve (AUC) increase approximately dose proportionally.
Specific groups of patients
Sex
No clinically relevant differences in vildagliptin pharmacokinetics were observed between healthy male and female subjects over a "wide range of age and body mass index (BMI). DPP-4 inhibition by vildagliptin is not affected." from sex.
Senior citizens
In healthy elderly subjects (≥ 70 years), the overall exposure of vildagliptin (100 mg once daily) increased by 32%, with an 18% increase in peak plasma concentration, compared to healthy young subjects (18 However, these changes are not considered clinically relevant. Inhibition of DPP-4 by vildagliptin is not affected by age.
Impaired liver function
The effect of hepatic impairment on vildagliptin pharmacokinetics was studied in patients with mild, moderate and severe hepatic impairment, based on Child-Pugh score (in the range of 6 for mild to 12 for severe), in compared to healthy subjects. In patients with mild and moderate hepatic impairment, exposure to vildagliptin after a single dose is decreased (by 20% and 8%, respectively), while for patients with severe hepatic impairment, exposure to vildagliptin is increased by 22%. The maximum change (decrease or increase) in vildagliptin exposure is ≥30%, which is not considered clinically relevant. There was no correlation between the severity of liver disease and changes in vildagliptin exposure.
Impaired renal function
An open-label, multiple-dose study was conducted to evaluate the pharmacokinetics of the lower therapeutic dose of vildagliptin (50 mg once daily) in patients with varying degrees of chronic renal impairment defined by creatinine clearance (mild: 50 to
Vildagliptin was removed by hemodialysis to a limited extent (3% over a 3-4 hour hemodialysis session starting 4 hours after dosing).
Ethnic groups
Limited data suggest that race does not have a major influence on vildagliptin pharmacokinetics.
05.3 Preclinical safety data -
Intra-cardiac impulse conduction delays were observed in dogs with a no effect dose of 15 mg / kg (7 times the human exposure based on Cmax).
An accumulation of foamy alveolar macrophages in the lungs was observed in rats and mice. The no effect dose was 25 mg / kg (5 times the human exposure based on AUC) in rats and 750 mg / kg (142 times the human exposure) in mice. Gastrointestinal symptoms, particularly soft stools, mucoid stools, diarrhea and, at higher doses, blood in the stool have been observed in dogs. A no-effect level has not been established.
In conventional genotoxicity studies in vitro And in vivo vildagliptin was not mutagenic. In rats, a fertility and early embryonic development study did not show that vildagliptin causes impairment of fertility, reproductive capacity or early embryonic development. Embryo-fetal toxicity was evaluated in rats and rabbits. In rats, an increased incidence of floating ribs was observed in association with a decrease in maternal body weight parameters, with a no effect dose of 75 mg / kg (10 times the human exposure). In rabbits, decreased fetal weight and skeletal changes, indicative of developmental delay, were observed only in the presence of severe maternal toxicity, with a no-effect dose of 50 mg / kg (9 times the human exposure). A study on pre- and postnatal development was performed in rats Effects were observed only in association with maternal toxicity with ≥ 150 mg / kg and including a transient reduction in body weight and reduced motor activity in the F1 generation.
A two-year carcinogenicity study in rats was performed with oral doses up to 900 mg / kg (approximately 200 times the human exposure at the maximum recommended dose). No increase in the incidence of tumors attributable to vildagliptin was observed. Another 2-year carcinogenicity study was conducted in mice with oral doses up to 1,000 mg / kg. An increase in the incidence of breast adenocarcinomas and hemangiosarcomas, with no effect doses of 500 mg / kg (59 times the human exposure) and 100 mg / kg (16 times the human exposure), respectively. The increased incidence of these tumors in mice was not considered to represent a significant risk to humans based on the lack of genotoxicity of vildagliptin and its major metabolite, the development of tumors in one species and all. high systemic exposure ratio at which tumors were observed.
In a 13-week toxicology study in monkeys cynomolgus skin lesions have been reported at doses ≥ 5 mg / kg / day. The lesions were consistently localized to the extremities (hands, feet, ears and tail). At a dose of 5 mg / kg / day (approximately equivalent to the human AUC after exposure to the 100 mg dose) only vesicles were observed. These regressed despite continuing treatment and were not associated with histopathological abnormalities. At doses ≥ 20 mg / kg / day (approximately 3 times the AUC in humans after exposure to the 100 mg dose), peeling and peeling of the skin, scabs and tail sores, with related histopathological changes, were noted. Necrotic lesions of the tail were observed at doses ≥ 80 mg / kg / day.
Over a 4-week recovery period, skin lesions did not regress in monkeys treated with 160 mg / kg / day.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Anhydrous lactose
Microcrystalline cellulose
Sodium starch glycolate (type A)
Magnesium stearate
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
3 years
06.4 Special precautions for storage -
Store in the original package to protect from moisture.
06.5 Nature of the immediate packaging and contents of the package -
Aluminum / aluminum blister (PA / Al / PVC // Al)
Available in packs containing 7, 14, 28, 30, 56, 60, 90, 112, 180 or 336 tablets and in multipacks containing 336 (3 packs of 112) tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling -
No special instructions.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Novartis Europharm Limited
Frimley Business Park
Camberley GU16 7SR
UK
08.0 MARKETING AUTHORIZATION NUMBER -
EU / 1/07/414 / 001-010
EU / 1/07/414/018
038144010
038144022
038144034
038144046
038144059
038144061
038144073
038144085
038144097
038144109
038144186
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: 26 September 2007
Date of most recent renewal: September 26, 2012
10.0 DATE OF REVISION OF THE TEXT -
D.CCE April 2015
