Indications:
Vildagliptin is indicated for the treatment of type 2 diabetes mellitus in adults:
- As monotherapy: In patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance.
- As dual therapy in combination with:
Metformin, in patients with insufficient glycemic control despite maximal tolerated dose of monotherapy with metformin.
Sulfonylurea, in patients with insufficient glycemic control despite maximal tolerated dose of a sulfonylurea and for whom metformin is inappropriate due to contraindications or intolerance.
Thiazolidinedione, in patients with insufficient glycemic control and for whom the use of a thiazolidinedione is appropriate.
- As triple therapy in combination with:
Sulfonylurea and metformin when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycemic control.
Vildagliptin is also indicated for use in combination with insulin (with or without metformin) when diet and exercise plus a stable dose of insulin do not provide adequate glycemic control.
Administration, dosage:
Administration: Oral use. Luciw-Cap capsule can be administered with or without a meal.
Dosage:
Adults:
When used as monotherapy, in combination with metformin, in combination with 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, administered as one dose of 50 mg in the morning and one dose of 50 mg in the evening.
When used in dual combination with a sulphonylurea, the recommended dose of vildagliptin is 50 mg 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 sulphonylurea, a lower dose of the sulphonylurea may be considered to reduce the risk of hypoglycaemia.
Doses higher than 100 mg are not recommended.
If a dose of Luciw-Cap is missed, it should be taken as soon as the patient remembers, adouble dose should not be taken on the same day.
The safety and efficacy of vildagliptin as triple oral therapy in combination with metformin and a thiazolidinedione have not been established.
Special populations:
Elderly (³ 65 years):
No dose adjustments are necessary in elderly patients.
Renal impairment:
No dose adjustment is required in patients with mild renal impairment (creatinine clearance ≥ 50 ml/min). In patients with moderate or severe renal impairment or with end-stage renal disease (ESRD), the recommended dose of vildagliptin is 50 mg once daily.
Hepatic impairment:
Vildagliptin should not be used in patients with hepatic impairment, including patients with pre-treatment alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 times the upper limit of normal (ULN).
Paediatric population:
Vildagliptin is not recommended for use in children and adolescents (< 18 years). The safety and efficacy of vildagliptin in children and adolescents (< 18 years) have not been established. No data available.
Contraindications:
Hypersensitivity to vildagliptin or any of excipients of the drug.
Warnings and precautions for use:
Precautions:
Vildagliptin is not a substitute for insulin in insulin-requiring patients. Vildagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Renal impairment:
There is limited experience in patients with ESRD on hemodialysis. Therefore, vildagliptin should be used with caution in these patients.
Hepatic impairment:
Vildagliptin should not be used in patients with hepatic impairment, including patients with pre-treatment ALT or AST > 3 times ULN.
Liver enzyme monitoring:
Rare cases of hepatic dysfunction (including hepatitis) have been reported. In these cases, the patients were generally asymptomatic without clinical sequelae and liver function test results returned to normal after discontinuation of treatment. Liver function tests (LFT) should be performed prior to the initiation of treatment with vildagliptin. Liver function should be monitored during treatment with vildagliptin at three-month intervals during the first year and periodically thereafter. Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return(s) to normal. Should an increase in AST or ALT of 3 times ULN or greater persist, withdrawal of vildagliptin therapy is recommended.
Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue vildagliptin.
Following withdrawal of treatment with vildagliptin and LFT normalisation, treatment with vildagliptin should not be reinitiated.
Cardiac failure:
A clinical trial of vildagliptin in patients with New York Heart Association (NYHA) functional class I-III showed that treatment with vildagliptin was not associated with a change in left-ventricular function or worsening of pre-existing congestive heart failure (CHF) versus placebo. Clinical experience in patients with NYHA functional class III treated with vildagliptin is still limited and results are inconclusive.
There is no experience of vildagliptin use in clinical trials in patients with NYHA functional class IV and therefore use is not recommended in these patients.
Skin disorders:
Skin lesions, including blistering and ulceration have been reported in extremities of monkeys in non-clinical toxicology studies. Although skin lesions were not observed at an increased incidence in clinical trials, there was limited experience in patients with diabetic skin complications. Furthermore, there have been post-marketing reports of bullous and exfoliative skin lesions. Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as blistering or ulceration, is recommended.
Acute pancreatitis:
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.
Hypoglycaemia:
Sulphonylureas are known to cause hypoglycaemia. 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.
Warning about excipients:
This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pregnancy and lactation:
Pregnancy:
There are no adequate data from the use of vildagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses. The potential risk for humans is unknown. Due to lack of human data, vildagliptin should not be used during pregnancy.
Lactation:
It is unknown whether vildagliptin is excreted in human milk. Animal studies have shown excretion of vildagliptin in milk. Therefore, vildagliptin should not be used during breast-feeding.
Fertility:
No studies on the effect on human fertility have been conducted for vildagliptin.
Effects on ability to drive and use machines:
No studies on the effects on the ability to drive and use machines have been performed. Patients who experience dizziness as an adverse reaction should avoid driving vehicles or using machines.
Interactions, incompatibilities of medicine:
Interaction of the drug with other drugs and other types of interactions:
Vildagliptin has a low potential for interactions with co-administered medicinal products. Since vildagliptin is not a cytochrome P (CYP) 450 enzyme substrate and does not inhibit or induce CYP 450 enzymes, it is not likely to interact with active substances that are substrates, inhibitors or inducers of these enzymes.
Combination with pioglitazone, metformin and glibenclamide
Results from studies conducted with these oral antidiabetics have shown no clinically relevant pharmacokinetic interactions.
Digoxin (P-glycoprotein substrate), warfarin (CYP2C9 substrate)
Clinical studies performed with healthy subjects have shown no clinically relevant pharmacokinetic interactions. However, this has not been established in the target population.
Combination with amlodipine, ramipril, valsartan or simvastatin
Drug-drug interaction studies in healthy subjects were conducted with amlodipine, ramipril, valsartan and simvastatin. In these studies, no clinically relevant pharmacokinetic interactions were observed after co-administration with vildagliptin.
Combination with ACE-inhibitors
There may be an increased risk of angioedema in patients concomitantly taking ACE-inhibitors.
As with other oral antidiabetic medicinal products, the hypoglycaemic effect of vildagliptin may be reduced by certain active substances, including thiazides, corticosteroids, thyroid products and sympathomimetics.
Incompatibilities:
Because there are no studies of drug incompatibility, do not mix this drug with other drugs.
Undesirable effects:
Summary of the safety profile
Safety data were obtained from a total of 3,784 patients exposed to vildagliptin at a daily dose of 50 mg (once daily) or 100 mg (50 mg twice daily or 100 mg once daily) in placebo-controlled trials of at least 12 weeks duration. Of these patients, 2,264 received vildagliptin as monotherapy and 1,520 patients 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.
The majority of adverse reactions in these trials were mild and transient, not requiring treatment discontinuations. No association was found between adverse reactions and age, ethnicity, duration of exposure or daily dose.
Rare cases of hepatic impairment (including hepatitis) have been reported. In these cases, patients were generally asymptomatic without clinical sequelae and liver function returned to normal after discontinuation of treatment. In monotherapy or combination controlled clinical trials lasting up to 24 weeks, the incidence of AST or ALT elevation equal to or greater than 3 times ULN (classified as present on at least 2 consecutive measurements or at the final on-treatment visit) 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 on vildagliptin at a similar rate to controls. A greater proportion of cases were reported when vildagliptin was administered in combination with an angiotensin converting enzyme inhibitor (ACE Inhibitor). The majority of events were mild in severity and resolved with ongoing vildagliptin treatment.
Tabulated list of adverse reactions
Side effects are classified according to frequency: Very common (ADR ≥ 1/10), common (1/100 ≤ ADR < 1/10), uncommon (1/1,000 ≤ ADR < 1/100), rare (1/10,000 ≤ ADR < 1/1,000), very rare (ADR < 1/10,000); can not be estimated from the available data “Not known”. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
- Association with metformin
Table 1. Adverse reactions in patients receiving vildagliptin at a dose of 100 mg daily in combination with metformin in double-blind trials (N = 208)
| Diseases of metabolism and nutrition | |
| Common | Hypoglycemia |
| Nervous system diseases | |
| Common | Tremor
Headache Dizziness |
| Uncommon | Fatigue |
| Gastrointestinal diseases | |
| Common | Nausea |
- Association with a sulfonylurea
Table 2. Adverse reactions reported in patients receiving vildagliptin 50 mg in combination with a sulphonylurea in double-blind trials (N = 170)
| Infections and infestations | |
| Very rare | Nasopharyngitis |
| Diseases of metabolism and nutrition | |
| Common | Hypoglycemia |
| Nervous system diseases | |
| Common | Tremor
Headache Dizziness Asthenia |
| Gastrointestinal diseases | |
| Uncommon | Constipation |
- Association with a thiazolidinedione
Table 3. Adverse reactions reported in patients receiving vildagliptin 100 mg daily in combination with a thiazolidinedione in double- blind trials (N = 158)
| Diseases of metabolism and nutrition | |
| Common | Weight increase |
| Uncommon | Hypoglycemia |
| Nervous system diseases | |
| Uncommon | Headache
Asthenia |
| Vascular diseases | |
| Common | Peripheral edema |
- Monotherapy
Table 4. Adverse reactions reported in patients receiving vildagliptin 100 mg daily as monotherapy in double-blind trials (N = 1,855)
| Infections and infestations | |
| Very rare | Upper respiratory tract infection
Nasopharyngitis |
| Diseases of metabolism and nutrition | |
| Uncommon | Hypoglycemia |
| Nervous system diseases | |
| Common | Dizziness |
| Uncommon | Headache |
| Vascular diseases | |
| Uncommon | Peripheral edema |
| Gastrointestinal diseases | |
| Uncommon | Constipation |
| Musculoskeletal and connective tissue disorders | |
| Uncommon | Arthralgia |
- Combination with metformin and a sulfonylurea
Table 5. Adverse reactions reported in patients receiving vildagliptin 50 mg twice daily in combination with metformin and a sulphonylurea (N = 175)
| Diseases of metabolism and nutrition | |
| Common | Hypoglycemia |
| Nervous system diseases | |
| Common | Dizziness
Tremor |
| Skin and subcutaneous tissue disorders | |
| Common | Hyperhidrosis |
| Systemic disorder | |
| Common | Asthenia |
- Association with insulin
Table 6. Adverse reactions reported in patients receiving vildagliptin 100 mg daily in combination with insulin (with or without metformin) in double-blind trials (N = 371)
| Diseases of metabolism and nutrition | |
| Common | Hypoglycaemia |
| Nervous system diseases | |
| Common | Headache, chills |
| Gastrointestinal diseases | |
| Common | Nausea, gastroesophageal reflux disease |
| Uncommon | Diarrhea, flatulence |
- Post-marketing experience
Table 7. Post-marketing adverse reactions
| Gastrointestinal diseases | |
| Not known | Pancreatitis |
| Hepatobiliary disorders | |
| Not known | Hepatitis (reversible after stopping drug administration)
Abnormal liver function tests (reversible after stopping drug administration) |
| Musculoskeletal and connective tissue disorders | |
| Not known | Myalgia |
| Skin and subcutaneous tissue disorders | |
| Not known | Urticaria
Exfoliative and bullous skin lesions, including bullous pemphigoid |
Overdose and management:
Information regarding overdose with vildagliptin is limited.
Symptoms:
Information on the likely symptoms of overdose was taken from a rising dose tolerability study in healthy subjects given vildagliptin for 10 days. At 400 mg, there were three cases of muscle pain and individual cases of mild and transient paraesthesia, fever, oedema and a transient increase in lipase levels. At 600 mg, one subject experienced oedema of the feet and hands, and increases in creatine phosphokinase (CPK), aspartate aminotransferase (AST), C-reactive protein (CRP) and myoglobin levels. Three other subjects experienced oedema of the feet, with paraesthesia in two cases. All symptoms and laboratory abnormalities resolved without treatment after discontinuation of the study medicinal product.
Management:
In the event of an overdose, supportive management is recommended. Vildagliptin cannot be removed by haemodialysis. However, the major hydrolysis metabolite (LAY 151) can be removed by haemodialysis.
Pharmacodynamics:
Pharmacotherapeutic group: Drugs used in diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitors.
ATC code: A10BH02.
Mechanism of action
The administration of vildagliptin results in a rapid and complete inhibition of DPP-4 activity, resulting in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).
Pharmacodynamic effects
By increasing the endogenous levels of these incretin hormones, vildagliptin enhances the sensitivity of beta cells to glucose, resulting in improved glucose-dependent insulin secretion. Treatment with vildagliptin 50 – 100 mg daily in patients with type 2 diabetes significantly improved markers of beta cell function including HOMA-β (Homeostasis Model Assessment–β), proinsulin to insulin ratio and measures of beta cell responsiveness from the frequently-sampled meal tolerance test. In non-diabetic (normal glycaemic) individuals, vildagliptin does not stimulate insulin secretion or reduce glucose levels.
By increasing endogenous GLP-1 levels, vildagliptin also enhances the sensitivity of alpha cells to glucose, resulting in more glucose-appropriate glucagon secretion.
The enhanced increase in the insulin/glucagon ratio during hyperglycaemia due to increased incretin hormone levels results in a decrease in fasting and postprandial hepatic glucose production, leading to reduced glycaemia.
The known effect of increased GLP-1 levels delaying gastric emptying is not observed with vildagliptin treatment.
Pharmacokinetics:
Absorption:
Following oral administration in the fasting state, vildagliptin is rapidly absorbed, with peak plasma concentrations observed at 1.7 hours. Food slightly delays the time to peak plasma concentration to 2.5 hours, but does not alter the overall exposure (AUC). Administration of vildagliptin with food resulted in a decreased Cmax (19%). However, the magnitude of change is not clinically significant, so that vildagliptin can be given with or without food. The absolute bioavailability is 85%.
Distribution:
The plasma protein binding of vildagliptin is low (9.3%) and vildagliptin distributes equally between plasma and red blood cells. The mean volume of distribution of vildagliptin at steady-state after intravenous administration (Vss) is 71 litres, suggesting extravascular distribution.
Biotransformation:
Metabolism is the major elimination pathway for vildagliptin in humans, accounting for 69% of the dose. The major metabolite (LAY 151) is pharmacologically inactive and is the hydrolysis product of the cyano moiety, accounting for 57% of the dose, followed by the glucuronide (BQS867) and the amide hydrolysis products (4% of dose). In vitro data in human kidney microsomes suggest that the kidney may be one of the major organs contributing to the hydrolysis of vildagliptin to its major inactive metabolite, LAY151. DPP-4 contributes partially to the hydrolysis of vildagliptin based on an in vivo study using DPP-4 deficient rats. Vildagliptin is not metabolised by CYP 450 enzymes to any quantifiable extent. Accordingly, the metabolic clearance of vildagliptin is not anticipated to be affected by co-medications that are CYP 450 inhibitors and/or inducers. In vitro studies demonstrated that vildagliptin does not inhibit/induce CYP 450 enzymes. Therefore, vildagliptin is not likely to affect metabolic clearance of co-medications metabolised by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 or CYP 3A4/5.
Elimination:
Following oral administration of [14C] vildagliptin, approximately 85% of the dose was excreted into the urine and 15% of the dose is recovered in the faeces. Renal excretion of the unchanged vildagliptin accounted for 23% of the dose after oral administration. After intravenous administration to healthy subjects, the total plasma and renal clearances of vildagliptin are 41 and 13 l/h, respectively. The mean elimination half-life after intravenous administration is approximately 2 hours. The elimination half-life after oral administration is approximately 3 hours.
Linearity/non-linearity:
The Cmax for vildagliptin and the area under the plasma concentrations versus time curves (AUC) increased in an approximately dose proportional manner over the therapeutic dose range.
Special populations:
Gender
No clinically relevant differences in the pharmacokinetics of vildagliptin were observed between male and female healthy subjects within a wide range of age and body mass index (BMI). DPP-4 inhibition by vildagliptin is not affected by gender.
Elderly
In healthy elderly subjects (≥ 70 years), the overall exposure of vildagliptin (100 mg once daily) was increased by 32%, with an 18% increase in peak plasma concentration as compared to young healthy subjects (18 – 40 years). However, these changes are not considered to be clinically relevant. DPP-4 inhibition by vildagliptin is not affected by age.
Hepatic impairment
The effect of impaired hepatic function on the pharmacokinetics of vildagliptin was studied in patients with mild, moderate and severe hepatic impairment based on the Child-Pugh scores (ranging from 6 for mild to 12 for severe) in comparison with healthy subjects. The exposure to vildagliptin after a single dose in patients with mild and moderate hepatic impairment was decreased (20% and 8%, respectively), while the exposure to vildagliptin for patients with severe impairment was increased by 22%. The maximum change (increase or decrease) in the exposure to vildagliptin is approximately 30%, which is not considered to be clinically relevant. There was no correlation between the severity of the hepatic disease and changes in the exposure to vildagliptin.
Renal impairment
A multiple-dose, open-label trial 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 < 80 ml/min, moderate: 30 to < 50 ml/min and severe: < 30 ml/min) compared to normal healthy control subjects.
Vildagliptin AUC increased on average 1.4, 1.7 and 2-fold in patients with mild, moderate and severe renal impairment, respectively, compared to normal healthy subjects. AUC of the metabolites LAY151 and BQS867 increased on average about 1.5, 3 and 7-fold in patients with mild, moderate and severe renal impairment, respectively. Limited data from patients with end stage renal disease (ESRD) indicate that vildagliptin exposure is similar to that in patients with severe renal impairment. LAY151 concentrations were approximately 2 – 3-fold higher than in patients with severe renal impairment.
Vildagliptin was removed by haemodialysis to a limited extent (3% over a 3 – 4 hour haemodialysis session starting 4 hours post dose).
Ethnic group
Limited data suggest that race does not have any influence on vildagliptin pharmacokinetics.
Storage conditions, shelf life, quality specification of the medicine:
Storage conditions: Protect from humidity and light, below 300C.
Shelf life: 36 months from the manufacture date.
Quality specification: In house.
A1203027001
