Date of approval: Month of year
Date of revision: January
Vigretin Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician.
Drug Name]
Generic name: Vildagliptin Tablets
English Name: Vildagliptin Tablets
Hanyu Pinyin: Weigelieting Pian
Ingredients
Active ingredient: Vildagliptin
Chemical name: (S)-1-[2-(3-hydroxyadamantan-1-ylamino)acetyl]pyrrolidine-2-carbonitrile
Chemical structure formula.
Molecular formula: C17H25N3O2
Molecular weight: 303.40
Properties
This product is a white to slightly yellow tablet.
【Indications】.
This product is indicated for the treatment of type 2 diabetes mellitus.
-When diet and exercise are not effective in controlling blood glucose, this product can be used as monotherapy.
-When metformin is used as monotherapy to the maximum tolerated dose and still cannot effectively control blood glucose, this product can be used in combination with metformin.
-When stable doses of insulin are not effective in controlling blood glucose, this product can be used in combination with insulin (with or without metformin)
-When stable dose of sulfonylurea still cannot effectively control blood sugar, this product can be used in combination with sulfonylurea.
Specification
50mg
Dosage and Administration
Adults
When vildagliptin is used as monotherapy or in combination with metformin, or in combination with insulin (with or without metformin), the recommended daily dose of vildagliptin is 100 mg, once in the morning and once in the evening, 50 mg each time.
When vildagliptin is used in combination with a sulfonylurea, the recommended dose of vildagliptin is 50 mg once daily, with morning dosing recommended. Lower doses of sulfonylureas may also be considered to reduce the risk of hypoglycemia.
Doses of 100 mg or more are not recommended.
This product can be taken with or without meals (see [Pharmacokinetics]).
Special Populations
Patients with renal insufficiency
Patients with mild renal insufficiency (creatinine clearance ≥ 50 ml/min) do not need to adjust the dose administered when using this product. The recommended dose in patients with moderate or severe renal insufficiency or in patients with end-stage renal disease (ESRD) on hemodialysis is 50 mg once daily (see [Pharmacokinetics]).
Patients with hepatic insufficiency
This product should not be used in patients with hepatic insufficiency, including patients with serum alanine aminotransferase (ALT) or serum aspartate aminotransferase (AST) greater than 3 times the upper limit of normal (ULN) prior to initiation of dosing (see [Precautions] and [Pharmacokinetics]).
[Adverse Reactions].
As reported in foreign literature.
Safety data for vildagliptin were obtained from multiple controlled clinical trials (studied for at least 12 weeks) in 3784 subjects who received vildagliptin 50 mg (once daily dosing) or 100 mg (50 mg twice daily dosing or 100 mg once daily dosing) daily during the course of the study. Of these patients, a total of 2264 were treated with vigagliptin monotherapy and 1520 were treated with vigagliptin in combination with other drugs. There were 2,682 patients treated with vigagliptin 100 mg administered once daily (50 mg twice daily or 100 mg once daily) and 1,102 patients treated with vigagliptin 50 mg once daily.
The major adverse reactions reported in these clinical trials were mild and transient and did not require discontinuation of the drug.
No adverse drug reactions were associated with patient age, race, duration of drug exposure, or daily dose administered.
Hepatic dysfunction, including hepatitis, has been reported rarely. In the reported cases, patients were generally clinically asymptomatic and without sequelae, and liver function test results returned to normal after discontinuation of the drug. Data from the monotherapy clinical study with a control group and the 24-week combination clinical study showed that in the 50 mg vildagliptin (administered once daily) dosing group, the 50 mg vildagliptin (administered twice daily) dosing group and all control groups, elevations of serum alanine aminotransferase (ALT) or serum aspartate aminotransferase (AST) ≥ the upper limit of normal (ULN) The incidence of 3-fold (i.e., these abnormalities in 2 consecutive test results or test results at the last treatment visit) was 0.2%, 0.3%, and 0.2%, respectively. Elevated transaminase levels are generally asymptomatic, non-progressive, and not accompanied by cholestasis or jaundice.
Angioedema was rarely reported, and the probability of this event was similar to that of controls. The frequency of this event was increased when vildagliptin was used concomitantly with angiotensin-converting enzyme inhibitors (ACE inhibitors). Angioedema was mild in most patients and resolved spontaneously with continued use of vildagliptin.
Summary Table of Adverse Drug Reactions in Clinical Trials
Adverse reactions in patients treated with vigagliptin (monotherapy or in combination with other drugs) in double-blind studies are listed in the table below according to MedDRA organ system classification and absolute frequency of occurrence. Within each system-organ classification, adverse reactions were ranked according to frequency of occurrence, with the most frequent adverse reactions occurring first. In each frequency group, adverse reactions were ranked in descending order of severity. In addition, the frequency classification of each adverse reaction was determined according to the following provisions (CIOMSIII): very common (≥1/10), common (≥1/100, <1/10), occasional (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), and unknown (not assessed by currently available data cannot be assessed).
Monotherapy
In controlled clinical studies of monotherapy, no increase in the overall incidence of study withdrawal due to adverse effects was seen in patients treated with vigagliptin 100 mg/day (0.3%) compared with the placebo group (0.6%) or the active drug control group (0.5%).
In the monotherapy clinical study, the incidence of hypoglycemic events was “incidental” at 0.4% (7 of 1855 patients) in patients receiving vildagliptin 100 mg/day, compared to 0.2% (2 of 1082 patients) in the active control or placebo groups, with no serious adverse events reported.
In the clinical trial, no change in body weight was observed in patients given 100 mg of vildagliptin daily (monotherapy) compared to the baseline period (-0.3 kg and -1.3 kg in the vildagliptin and placebo groups, respectively).
Table 1 Adverse reactions reported by patients receiving vildagliptin monotherapy (100 mg/day) in a double-blind clinical study (N=1855)
Neurologic lesions Common vertigo Occasional headache Digestive lesions Occasional constipation Muscle and connective tissue disorders Occasional arthralgia Metabolic and nutritional disorders Occasional hypoglycemia Infectious and infectious diseases Very rare Upper respiratory tract infections Very rare Nasopharyngitis Vascular lesions Occasional peripheral edema Results of long-term clinical studies of vildagliptin monotherapy showed that no additional drug was identified during the two-year study period safety concerns or unanticipated risks.
In combination with metformin
In the controlled clinical study of vildagliptin 100 mg/day + metformin combination, no patients in either the vildagliptin 100 mg/day + metformin treatment group or the placebo + metformin treatment group withdrew from the study due to adverse effects.
In the clinical study, the incidence of hypoglycemia was “common” (1%) in patients treated with vildagliptin + metformin and “occasional” (0.4%) in subjects treated with placebo + metformin. No serious hypoglycemic events were reported in the vildagliptin-treated group.
In the clinical study, no change in body weight was observed in patients given vildagliptin 100 mg/day + metformin compared to the baseline period (+0.2 kg and -1.0 kg in the vildagliptin and placebo groups, respectively).
Table 2 Adverse reactions reported in patients treated with the combination of vildagliptin (100 mg/day) and metformin in double-blind clinical studies (N=208)
Neurological lesions Common tremor, headache, vertigo Occasional weakness Digestive lesions Common nausea Metabolic and nutritional disorders Common hypoglycemia Combined with sulfonylureas
In the clinical controlled study of the combination of vildagliptin 50 mg + sulfonylurea, the incidence of study withdrawal due to adverse reactions in the vildagliptin 50 mg + sulfonylurea and placebo + sulfonylurea groups was
0.6% and 0%.
In the clinical study, the incidence of hypoglycemia in patients in the vildagliptin 50 mg + sulfonylurea group and the placebo + sulfonylurea group was 1.2% and 0.6%, respectively. No serious hypoglycemic events were reported in the treatment group of vildagliptin.
In the clinical study, patients were given vildagliptin 50 mg/day + sulfonylurea with no change in weight compared to the baseline period (the amount of weight change was -0.1 kg and -0.4 kg in the vildagliptin and placebo groups, respectively).
Table 3 Adverse reactions reported in patients treated with the combination of vildagliptin (50 mg/day) and sulfonylureas in a double-blind clinical study (N=170)
Infectious and infectious diseases Very rare nasopharyngitis Neurologic lesions Common tremor, headache, vertigo, and malaise Digestive lesions Occasional constipation Systemic and injection site lesions Common debilitating metabolic and nutritional system disorders Common hypoglycemia in combination with thiazolidinediones
In the clinical controlled study of the combination of vigagliptin 100 mg/day + thiazolidinediones, no patients withdrew from the clinical study due to adverse effects in either the vigagliptin 100 mg/day + thiazolidinediones group or the placebo + thiazolidinediones group.
In the clinical study, the frequency of hypoglycemia was “occasional” (0.6%) in patients treated with vildagliptin + pioglitazone and “common” (1.9%) in patients treated with placebo + pioglitazone. No serious hypoglycemic events were reported in the vildagliptin-treated group.
In the add-on treatment study with pioglitazone, patients in the placebo and vildagliptin (100 mg/day) groups showed an absolute weight gain of 1.4 kg and 2.7 kg, respectively.
The addition of pioglitazone (45 mg once daily) to the highest dose of pioglitazone (100 mg/day) resulted in a 7.0% incidence of peripheral edema in patients, compared with a 2.5% incidence of this event in patients on pioglitazone alone.
Table 4 Adverse reactions reported in patients treated with the combination of vildagliptin (100 mg/day) and thiazolidinediones in a double-blind clinical study (N=158)
Neurological disorders Occasional headache, malaise Metabolic and nutritional disorders Common weight gain Occasional hypoglycemic vascular lesions Common peripheral edema
In combination with insulin
In controlled clinical trials of vildagliptin (50 mg twice daily) in combination with insulin (with or without metformin), the overall incidence of study withdrawal due to adverse reactions was 0.3% in the vildagliptin-treated group, while there were no subject withdrawals in the placebo group.
The incidence of hypoglycemia was similar between the two dosing groups (14.0% in the vildagliptin-treated group and 16.4% in the placebo group). Two subjects in the vildagliptin-treated group developed severe hypoglycemia, while six subjects in the placebo group developed severe hypoglycemia.
At the end of the study, there was little effect of the drug on mean body weight (+0.6 kg in the vigagliptin group and no change in the placebo group compared to baseline).
Table 5 Adverse reactions reported by patients treated with this product (50 mg twice daily) in combination with insulin (with or without metformin) (N=371)
Neurologic lesions Common headache Digestive lesions Common nausea, gastroesophageal reflux disease Occasional diarrhea, gastrointestinal distention Systemic lesions and administration site lesions Common chills Examination Common decreased blood glucose
Triple combination with metformin and sulfonylurea
No cases of withdrawal from the study due to adverse effects were reported in the vincristine + metformin + glimepiride treatment group compared to 0.6% in the placebo + metformin + glimepiride treatment group.
The occurrence of hypoglycemia was more common in both treatment groups (5.1% in the vildagliptin + metformin + glimepiride treatment group and 1.9% in the placebo + metformin + glimepiride treatment group), with one severe hypoglycemic event reported in the vildagliptin group.
At the end of the study, there was little effect of the drug on mean body weight (+0.6 kg in the vildagliptin-treated group and -0.1 kg in the placebo group).
Table 6 Adverse reactions reported by patients treated with this product (50 mg twice daily) and metformin and sulfonylureas (n=157)
Neurological lesions Common dizziness and tremor Systemic lesions and abnormalities at the site of administration Common debilitating metabolic and nutritional system disorders Common hypoglycemia Skin and subcutaneous tissue lesions Common excessive sweating Spontaneous reports and adverse drug reactions from literature case sources – post-marketing experience (frequency of occurrence unknown)
The following sources of adverse drug reactions are spontaneous case reports of this product and post-marketing experience with literature cases. Since these reactions were spontaneous reports from an unknown number of people, it is not possible to evaluate their incidence with certainty, so they are classified as of unknown frequency.
Hepatitis, all were able to return to normal after discontinuation of the drug. (Please see [Precautions]).
Urticaria, maculopapular or exfoliative skin lesions, including herpetiform aspergillosis.
Pancreatitis
Arthralgia, sometimes more severe.
[Contraindications].
Contraindicated if you are hypersensitive to this product or any of the ingredients in this product.
Precautions]
General principles
This product should not be used as a substitute for insulin in patients who require insulin supplementation. This product is not suitable for use in patients with type 1 diabetes and should not be used for the treatment of diabetic ketoacidosis.
Patients with renal insufficiency
Use with caution in patients with moderate or severe renal insufficiency or in patients with end-stage renal disease (ESRD) requiring hemodialysis treatment (see [Dosage]).
Patients with hepatic insufficiency
This product should not be used in patients with hepatic insufficiency, including patients with serum alanine aminotransferase (ALT) or serum aspartate aminotransferase (AST) greater than 3 times the upper limit of normal (ULN) prior to initiation of dosing.
Liver Enzyme Monitoring
Hepatic dysfunction (including hepatitis) has been reported rarely during the use of this product. In the reported cases, patients generally did not develop clinical symptoms and had no sequelae. Liver function test results returned to normal after discontinuation of the drug. Liver function tests should be performed prior to administration of this product to understand the patient’s baseline condition. Liver function should be measured every three months during the first year of use and periodically thereafter. Patients with elevated aminotransferases should be retested to review the test results and the frequency of liver function testing should be increased thereafter until abnormal results return to normal. It is advisable to discontinue this product when a patient’s serum alanine aminotransferase (ALT) or serum aspartate aminotransferase (AST) exceeds three times the upper limit of normal (ULN) or remains elevated.
Patients who develop jaundice or other symptoms suggestive of liver dysfunction should discontinue this product and need to contact their primary care physician immediately for examination.
After discontinuation of this product, it is not recommended to resume treatment with this product after liver function tests have returned to normal.
Heart Failure
A clinical trial of vildagliptin in patients with New York Heart Association (NYHA) cardiac function class I-III showed no correlation between treatment with vildagliptin and changes in left ventricular function or worsening of preexisting congestive heart failure (CHF) compared to the placebo group. The rate of reported adverse cardiac events was slightly higher in the vildagliptin-treated group than in the placebo group in patients with NYHA cardiac function class III; however, the imbalance in baseline cardiovascular risk between the placebo and vildagliptin groups and the small number of patients in the NYHA class III subgroup make it impossible to draw definitive conclusions.
Clinical trials of vildagliptin have not been conducted in patients with NYHA cardiac class IV and therefore it is not recommended for this patient population.
Skin Diseases
Skin lesions, including blisters and ulcers, on the extremities have been reported in preclinical toxicology studies of vildagliptin in monkeys (see [Pharmacologic Toxicology]). Although no abnormal increase in the incidence of skin lesions was observed in clinical studies, experience with the use of vigagliptin in patients with comorbid diabetic skin complications remains relatively limited. In addition, blistering and peeling have been reported post-marketing. Therefore, it is recommended that diabetic patients using this product should be monitored for skin lesions (e.g., blisters or ulcers) with special attention along with their usual care.
Pancreatitis
Post-marketing experience has previously reported spontaneous acute pancreatitis. Patients should be informed in advance of the clinical signs of acute pancreatitis: persistent, severe abdominal pain.
Discontinuation of vildagliptin has been reported after the disappearance of symptoms of pancreatitis. If pancreatitis is suspected, treatment with vigagliptin and other medications that may cause pancreatitis should be discontinued.
Hypoglycemia
Sulfonylureas are known to cause hypoglycemia. Patients receiving vildagliptin in combination with a sulfonylurea are considered to be at risk of hypoglycemia. Therefore, lower doses of sulfonylureas may be considered to reduce the risk of hypoglycemia.
Excipients
The tablets of this product contain lactose. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this product.
Effects on driving and ability to operate machinery
There are no studies on the effects of this product on the ability of patients to drive and operate machinery. Patients who experience vertigo after taking this drug should avoid driving or operating machinery.
Pregnant women and nursing mothers
Pregnancy
There are few data related to the use of Vigretin in pregnant women. Results from animal studies have shown reproductive toxicity at high doses of vildagliptin. The potential risk to humans is unknown. Due to the lack of data on its use in humans, it should not be used during pregnancy.
Lactation
It is not known whether vildagliptin is excreted in humans through breast milk. Results from animal studies indicate that vildagliptin is excreted in breast milk. Therefore, this product should not be used during lactation.
Fertility
No studies have been conducted to correlate vildagliptin with fertility in humans, and no reliable references are available.
Pediatric Use]
Due to the lack of safety and efficacy data, this product is not recommended for use in pediatric and adolescent (under 18 years of age) patients.
Geriatric use]
Clinical studies of this product in patients aged ≥65 years and ≥75 years showed no significant differences in safety, tolerability and efficacy in elderly patients compared to young patients. No dose adjustment is required in elderly patients (see [Pharmacokinetics]).
Drug Interactions]
Vigliptin has a low potential for interaction with other drugs. Because vildagliptin is not a substrate of the cytochrome P (CYP) 450 enzyme family and it does not induce or inhibit CYP450 enzymes, it is unlikely to interact with drugs whose active ingredients are substrates, inhibitors, or inducers of these enzymes.
In addition, vildagliptin is unlikely to affect the metabolic clearance of drugs used concomitantly with it and dependent on CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1, or CYP 3A4/5 for metabolism. Drug-drug interactions between commonly prescribed drugs or drugs with a narrow therapeutic window and viglitazone in patients with type 2 diabetes were investigated. The results of the study showed that no clinically meaningful drug-drug interactions were observed after concomitant administration of other oral hypoglycemic agents (gliphenylurea, pioglitazone, metformin hydrochloride), amlodipine, digoxin, ramipril, simvastatin, valsartan, or warfarin with viglitazone.
Combination with pioglitazone, metformin and gliphenylurea
Results from clinical trials have shown that no clinically meaningful pharmacokinetic interactions were observed when vildagliptin was administered concomitantly with the oral antidiabetic drugs pioglitazone, metformin, and gliphenylurea.
Digoxin (P-glycoprotein substrate), warfarin (CYP 2C9 substrate)
Results of clinical studies in healthy subjects have shown no clinically meaningful pharmacokinetic interactions following concomitant administration of vildagliptin with these two drugs. However, this study has not been conducted in the target population.
Combination with Amlodipine, Ramipril, Valsartan and Simvastatin
Drug-drug interaction studies with amlodipine, ramipril, valsartan, and simvastatin have also been conducted in healthy subjects. In these studies, no clinically meaningful pharmacokinetic interactions were observed following concomitant administration of the above drugs with viglitazene.
Similar to other oral hypoglycemic agents, the hypoglycemic effect of vigagliptin may be diminished by certain specific drugs, including thiazide diuretics, corticosteroids, thyroid hormones and sympathomimetic drugs.
[Drug Overdose].
Signs and symptoms
In a study conducted in healthy subjects (7-14 subjects in each treatment group), the dosing regimen was 25, 50, 100, 200, 400 and 600 mg administered once daily for 10 days. The dose of 200 mg was well tolerated by the subjects. In the 400 mg dose group, three patients developed muscle pain, and all patients exhibited mild and transient sensory abnormalities, fever, edema and transient elevated lipase levels (2 x ULN). In the 600 mg dose group, one subject developed hand and foot edema and increased levels of creatine phosphokinase (CPK), aspartate aminotransferase (AST), C-reactive protein, and myoglobin. Three other subjects developed foot edema, and two of these subjects also developed concomitant sensory abnormalities. After discontinuation of the test drug, all subjects recovered from the symptoms and abnormal laboratory results without treatment.
Treatment
When an overdose occurs, adjunctive management measures are recommended. Vigliptin cannot be removed by dialysis, but its major hydrolysis metabolite (LAY 151) can be removed by dialysis.
[Clinical trials].
Foreign clinical studies have reported that
More than 15,000 patients with type 2 diabetes have participated in double-blind, placebo or active drug-controlled clinical studies lasting more than 2 years. Over the course of the study, more than 9,000 patients received vildagliptin (administered at a dose of 50 mg once daily, 50 mg twice daily or 100 mg once daily). A total of more than 5,000 male patients and more than 4,000 female patients received either 50 mg or 100 mg of vildagliptin daily. More than 1,900 of these patients treated with 50 mg or 100 mg daily of vigagliptin were 65 years of age or older. These studies included vildagliptin monotherapy in patients with type 2 diabetes who were not receiving medication, as well as combination therapy when other glucose-lowering drugs were not effective in controlling blood glucose.
Overall, it appeared that the combination of vildagliptin and metformin improved glycemic control in patients, using the decline in HbA1C of patients at the end of the study relative to the baseline period as an evaluation metric. In a 24-week clinical trial, vildagliptin 50 mg twice daily (bid), vildagliptin 50 mg once daily (qd) and placebo were examined in comparison as add-on therapy for patients with type 2 diabetes who had previously failed to receive metformin monotherapy. The mean HbA1C at baseline for patients in this trial was 8.4%. At the week 24 study endpoint, the mean decrease in HbA1C from baseline was 0.9%, while the placebo-corrected mean decrease in HbA1C was 1.1%, both statistically significant (p < 0.001).
In a 24-week clinical study, vildagliptin (50 mg twice daily) was compared with pioglitazone (30 mg once daily) in patients who were not effectively controlled with metformin (mean daily dose: 2020 mg). The mean HbA1C was reduced by 0.9% and 1.0% relative to the mean baseline HbA1C (8.4%) in the vildagliptin + metformin-treated and pioglitazone + metformin-treated groups, respectively. Patients treated with pioglitazone and metformin gained 1.9 kg, while those treated with vildagliptin and metformin gained only 0.3 kg.
In a two-year clinical trial, vildagliptin (50 mg twice daily) and glimepiride (up to 6 mg/day, two-year average dose: 4.6 mg) were compared in patients already receiving metformin (average daily dose: 1894 mg). One year after the start of the study, patients in the vildagliptin + metformin treatment group and the glimepiride + metformin treatment group had an average reduction in HbA1C of 0.4% and 0.5%, respectively, relative to the mean HbA1C at baseline (7.3%). The amount of weight change was -0.2 kg and +1.6 kg for patients who added viglitazone and glimepiride to the regimen, respectively. the incidence of hypoglycemia was significantly lower in patients in the viglitazone treatment group (1.7%) compared to the glimepiride treatment group (16.2%). At the end of the study (2 years), HbA1C was similar to baseline values in both treatment groups, and the difference between the patients’ weight change and the incidence of hypoglycemia continued to be maintained.
In a 52-week clinical trial, vildagliptin (50 mg twice daily) and gliclazide (mean daily dose: 229.5 mg) were compared in patients whose disease could not be controlled with metformin alone (metformin dose of 1928 mg daily at baseline). After 1 year of the study, patients in the vildagliptin+metformin treatment group had a mean reduction in HbA1C of 0.81% (mean HbA1C at baseline: 8.4%), whereas patients in the gliclazide+metformin administration group had a mean reduction in HbA1C of 0.85% (mean HbA1C at baseline: 8.5%), which had achieved statistically non-inferiority (95% CI -0.11-0.20). The amount of weight change in patients in the vildagliptin administration group was +0.1 kg, compared with +1.4 kg in the gliclazide administration group.
In a 24-week, randomized, double-blind, placebo-controlled study, the safety and efficacy of vildagliptin 50 mg twice daily in combination with a stable dose of basal or premixed insulin (with or without metformin) was evaluated in 449 patients with a mean daily dose of insulin of 41 units. The mean placebo-corrected reduction in HbA1c was 0.72% in the total population (mean HbA1c at baseline was 8.8%). In the subgroup treated with insulin with or without metformin, the mean placebo-corrected reduction in HbA1c was 0.63% and 0.84%, respectively. The incidence of hypoglycemia in the total population was 8.4% and 7.2% in the vildagliptin and placebo groups, respectively. Patients in the vildagliptin group did not gain weight (+0.2 kg), while those in the placebo group lost weight (-0.7 kg).
The safety and efficacy of vildagliptin combined with glimepiride (2 mg or 4 mg) treatment was evaluated in a 24-week randomized, double-blind, placebo-controlled trial. At the study endpoint, after multifactorial correction, HbA1c was reduced by 0.58% from baseline in the vildagliptin 50 mg, once-daily add-on treatment group (n=132) (mean baseline HbA1c was 8.5%), with a statistically significant difference in mean change in HbA1c relative to baseline between the two groups compared with the placebo add-on treatment group (n=144) (-0.6%, p < 0.05).
Cardiovascular risk
In an independent prospective meta-analysis of adjudicated cardiovascular events from 37 phase III and IV (both monotherapy and combination therapy) clinical studies lasting more than 2 years, 9599 patients with type 2 diabetes mellitus (T2DM) were treated with vildagliptin 50 mg qd or 50 mg bid and 7102 patients were treated with a control agent (placebo or active control agent). The results showed no association between vildagliptin treatment and increased cardiovascular risk. The adjudicated major adverse cardiovascular event (MACE), a composite endpoint including acute myocardial infarction, stroke, or cardiovascular death, was similar in the vildagliptin-treated group to the control group combined with the active drug and placebo, with a Mantel-Haensze risk ratio (M-H RR) of 0.82 (95% confidence interval 0.61-1.11), demonstrating the cardiovascular safety of vildagliptin. MACE occurred in 83 of 9599 vildagliptin-treated patients (0.86%) and in 85 of 7102 control-treated patients (1.20%). each individual event assessed in MACE showed no increased cardiovascular risk with vildagliptin (similar M-H RR). Definitive heart failure (HF) events were defined as HF requiring hospitalization or new-onset HF, which occurred in 41 (0.43%) of vildagliptin-treated patients and 32 (0.45%) of control-treated patients, with an M-H RR of 1.08 (95% CI 0.68-1.70), indicating no increased risk of HF in vildagliptin-treated patients.
Pharmacology and Toxicology]
Pharmacological effects
Vigliptin is a selective dipeptide-peptidase-4 (DPP-4) inhibitor, which rapidly inhibits DPP-4 activity after administration and increases the levels of fasting and postprandial endogenous glucagon GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide), thereby increasing β-cell sensitivity to glucose and promoting glucose-dependent insulin secretion. . By increasing endogenous GLP-1 levels, vigagliptin is also able to increase the sensitivity of α-cells to glucose, resulting in an increased fit between glucose levels and glucagon secretion.
During hyperglycemia, vildagliptin increases the insulin/glucagon ratio by elevating intestinal hypoglycemic levels, leading to decreased fasting and postprandial hepatic glucose production, which in turn lowers blood glucose.
Elevated levels of GLP-1 are known to cause delayed GI emptying, but this did not occur after vildagliptin administration.
Toxicological studies
General Toxicology
Delayed cardiac conduction was seen in dogs following administration of a no-effects dose of 15 mg/kg (7 times the human exposure level at a dose of 100 mg based on Cmax (below)).
In rats and mice, an increase in alveolar macrophages was observed after administration, with a no-effects dose of 25 mg/kg (5 times the human exposure level based on AUC) and 750 mg/kg (142 times the human exposure level), respectively.
Gastrointestinal signs, particularly soft stools, mucus stools, and diarrhea, were seen in dogs after drug administration, and blood in the stool was found in the high-dose group. A non-responsive dose of the drug could not be established.
In a 13-week toxicity trial in short-tailed monkeys, skin lesions were seen at doses of vildagliptin ≥ 5 mg/kg/day, generally on the extremities (hands, feet, ears, and tail). only reversible blistering was seen at a dose of 5 mg/kg/day (approximately equivalent to human exposure levels), and histopathological examination showed no abnormalities. At doses ≥ 20 mg/kg/day (approximately 3 times the human exposure level), skin flaking, skin flaking, crusting and caudal ulceration were seen, along with corresponding histopathological changes. Caudal necrosis was seen at doses ≥80 mg/kg/day. During a 4-week recovery period, skin damage failed to recover in animals in the 160 mg/kg/day dosing group.
Genotoxicity
Routine in vitro and in vivo genotoxicity tests with vildagliptin were negative.
Reproductive toxicity
No effects on fertility, reproductive behavior, or early embryonic development were observed in the fertility and early embryonic development toxicity tests conducted in rats. In the rat and rabbit embryo-fetal development toxicity assay, rib deformities were observed in fetuses with weight loss in parental animals at a no-response dose of 75 mg/kg (10 times the human exposure level); in rabbits, weight loss in fetuses and skeletal deformities suggestive of developmental delay were observed only in the presence of severe maternal toxicity at a no-response dose of 50 mg/kg (9 times the human exposure level). (9 times the human exposure level). In perinatal toxicity tests in rats, maternal toxicity, transient weight loss in the F1 generation and reduced autonomic activity were observed at doses of vildagliptin ≥150 mg/kg.
Carcinogenicity
In a 2-year carcinogenicity study of vildagliptin in rats at oral doses up to 900 mg/kg (approximately 200 times the maximum recommended human dose exposure), no increase in tumor incidence was observed in the test animals. An additional 2-year study of the carcinogenicity of vildagliptin was conducted in mice at oral doses of the drug up to 1000 mg/kg, and an increased incidence of breast cancer and angiosarcoma was observed at no-adverse-effect doses of 500 mg/kg (59 times the human exposure level) and 100 mg/kg (16 times the human exposure level), respectively. Due to the lack of information on the genotoxicity of vildagliptin and its major metabolites, the occurrence of the above tumors in only one species and the high rate of systemic exposure at the time the tumors were observed, the increased incidence of the above tumors in mice does not represent an increased risk in humans.
Pharmacokinetics]
Absorption
After oral administration on an empty stomach, vildagliptin is rapidly absorbed, with peak plasma drug concentrations occurring 1.7 hours after dosing. Food slightly delays the peak time up to 2.5 hours, but does not alter the total exposure level (AUC) of the drug. The change in peak plasma drug concentration Cmax by 19% after feeding was not clinically significant and therefore vildagliptin could be administered with or without food. The absolute bioavailability of the drug was 85%.
Distribution
The binding of vildagliptin to plasma proteins is low (9.3%) and the drug is uniformly distributed in plasma and red blood cells. After intravenous administration, the mean steady-state volume of distribution (Vss) of vildagliptin was 71 liters, suggesting that the drug is able to be distributed outside the body circulation.
Metabolism
Metabolism is the major route of elimination of vildagliptin in the body, accounting for approximately 69% of the administered dose. The major metabolite of vildagliptin (LAY 151), which is not pharmacologically active, is the hydrolysis product of the cyano group, accounting for approximately 57% of the administered dose, and the minor metabolite is the amino hydrolysis product (approximately 4% of the administered dose). In vitro studies with human renal microsomal enzymes suggest that the kidney may be one of the major organs involved in the hydrolysis of vildagliptin, yielding the major inactive metabolite LAY 151. Results from in vivo experiments using DPP-4-deficient rats suggest that the hydrolysis of vildagliptin is to some extent related to DPP-4. Vildagliptin is not metabolized by CYP 450. Therefore, the metabolic clearance of vildagliptin is not affected by CYP 450 inhibitors and/or inducers in the co-administered drugs. Results from in vitro studies indicate that vildagliptin has no inhibitory or inducing effects on the CYP 450 enzyme system. Therefore, vildagliptin does not affect the metabolic clearance of co-administered drugs via CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1, or CYP 3A4/5.
Elimination
After oral administration of [14C]viglitazone, approximately 85% of the drug is excreted in the urine and 15% is able to be recovered from the feces. After oral administration, approximately 23% of vildagliptin in its prodrug form was excreted from the kidneys. The total plasma and renal clearance of the drug after intravenous administration of vildagliptin to healthy subjects was 41 L/h and 13 L/h, respectively. The mean elimination half-life of vildagliptin after intravenous administration was approximately 2 hours. After oral administration, the elimination half-life of vildagliptin was approximately 3 h.
Linearity
Within the therapeutic dose range, the peak plasma drug concentration and the area under the plasma drug concentration-to-time curve (AUC) of vildagliptin increase approximately proportionally with increasing dose.
Special Populations
Gender
No gender-related clinical differences in the pharmacokinetic parameters of vildagliptin were observed in healthy male and female subjects within a wide age range and body mass index (BMI). The inhibitory effect of vildagliptin on DPP-4 was not affected by gender.
Age
Vigagliptin (100 mg/day) was associated with a 32% increase in total exposure levels and an 18% increase in peak plasma drug concentrations in healthy elderly subjects (≥70 years of age) compared to young healthy subjects (18-40 years of age). The study concluded that these changes were not clinically significant and that the inhibitory effect of vildagliptin on DPP-4 was not influenced by age.
Obesity
BMI had no effect on the pharmacokinetic parameters of vildagliptin. The inhibitory effect of vildagliptin on DPP-4 is not influenced by BMI.
Patients with hepatic insufficiency
The effect of hepatic insufficiency on the pharmacokinetic parameters of vigagliptin was examined in patients with mild, moderate and severe hepatic insufficiency [scores between 6 (mild) and 12 (severe) according to Child-Pugh score grading] compared with healthy subjects. After a single dose of vildagliptin, drug exposure levels were reduced in patients with mild and moderate hepatic insufficiency (20% and 8%, respectively), but drug exposure levels were elevated by 22% in patients with severe hepatic insufficiency. The maximum amount of change (increase or decrease) in vildagliptin exposure levels was approximately 30%, and the study concluded that this result was not clinically significant. There was no correlation between the change in vildagliptin exposure levels and the severity of hepatic insufficiency in patients.
It should not be administered to patients with hepatic insufficiency, including patients with serum alanine aminotransferase (ALT) or serum aspartate aminotransferase (AST) greater than 3 times the upper limit of normal (ULN) prior to initiation of dosing.
Patients with renal insufficiency
Compared to normal healthy subjects, vildagliptin increased the mean AUC by 1.4, 1.7, and 2-fold in patients with mild, moderate, and severe renal insufficiency, respectively, and the metabolite LAY151 increased the AUC by 1.6, 3.2, and 7.3-fold, and BQS867 increased the AUC by 1.4, 2.7, and 7.3-fold. Limited data in patients with end-stage renal disease (ESRD) suggest that their vildagliptin exposure is similar to that of patients with severe renal insufficiency. lAY151 concentrations in ESRD patients are approximately 2 to 3 times higher than in patients with severe renal insufficiency. See [Dosage] for details on dosing in patients with renal insufficiency.
Hemodialysis may remove vildagliptin to limited levels (3% by 3-4 hours of hemodialysis 4 hours after dosing).
Elderly Patients
This product (100 mg/day) was associated with a 32% increase in total exposure levels and an 18% increase in peak plasma drug concentrations in healthy elderly subjects (≥70 years of age) compared to young healthy subjects (18-40 years of age). The study concluded that these changes were not clinically significant and that the inhibitory effect of this product on DPP-4 was not affected by age.
Pediatric Patients
No pharmacokinetic data are available for this product in children.
Race
Based on the limited data available, there is no significant effect of racial factors on the pharmacokinetic properties of vildagliptin.
Storage
Seal and store at room temperature (10~30℃).
Packaging
Double aluminum packaging. 14 tablets/plate, 1 plate/box.
Expiration date
24 months
【Execution standard
【Approval number】
【Marketing license holder
Company Name: Beijing Tide Pharmaceutical Co.
Address: No. 8, Rongjing East Street, Beijing Economic and Technological Development Zone, Beijing, China
Manufacturer
Company Name: Beijing Tide Pharmaceutical Co.
Production Address: No. 8, Rongjing East Street, Beijing Economic and Technological Development Zone, Beijing, China
Postal Code: 100176
Tel: (010) 67880648
Fax number: (010) 67863609
Website: www.tidepharm.com