VYSOV-XR Tablets (Vildagliptin)

Table of Content

Diabetes is a chronic metabolic disease that affects 463 million people globally and over 77 million people from India. Type 2 diabetes mellitus (T2DM) is a group of metabolic disorders characterized by high blood glucose levels. As per ICMR-INDIAB study, around 70% of individuals with T2DM do not have adequate glycaemic control (HbA1c <7%).

Current guidelines by major diabetes organizations recommend metformin as a first line therapy for management of T2DM along with lifestyle modifications. Dipeptidyl peptidase 4 (DPP-4) inhibitors are an oral antihyperglycaemic drug class that helps in achieving glucose control without increasing the risk of hypoglycaemia and weight gain. They inhibit the degradation of gut hormones viz. glucagon-like peptide 1 and glucose-dependent insulinotropic peptide, thus increasing insulin secretion and inhibiting glucagon secretion. Both these actions occur only during hyperglycaemia, thus reducing the risk of hypoglycaemia.

Vildagliptin is one of the earliest approved DPP-4 inhibitors that has shown sustained efficacy and tolerability in clinical trials as well as real-world studies. It has proven efficacy and safety data as an add-on in patients uncontrolled on monotherapy, as a component of triple therapy as well as add-on to insulin therapy. Due to its proven safety profile, it is also considered as an effective T2DM drug choice in elderly, those with renal impairment and those who fast for long periods (such as during Ramadan).

Improving adherence to antidiabetes medication is essential, as this has been shown to result in improved glycemic control and consequently lead to a reduction in disease- related events, hospitalizations, mortality and healthcare costs. Adherence to medical regimen is important in the optimal management of diabetes, and medication dosing frequency has an important effect on medication adherence. Once-daily medical regimens result in up to twice as many adherent days as more frequent dosing regimens.

Vildagliptin sustained release formulation is a DCGI approved formulation and based on pharmacokinetic data of Vysov-XR, it is concluded that the test product vildagliptin sustained release 100 mg tablet (once daily) is bioequivalent to the reference product (vildagliptin 50mg given twice daily).

Vysov-XR (Vildagliptin sustained release 100 mg tablets) is indicated as an adjunct to diet and exercise to improve glycaemic control in patients with T2DM. The recommended dose of Vysov-XR is 100 mg once daily. The maximum daily dose of Vysov-XR is 100 mg.

 

To be sold by retail on the prescription of Registered Medical Practitioner only

Qualitative and Quantitative Composition

VYSOV-XR 100 mg

Each film coated sustained-release  tablet contains:

Vildagliptin……………………100 mg

Dosage Form and Strength

Oral tablet

Clinical Particulars

Therapeutic Indication

VYSOV-XR is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type-II diabetes mellitus.

Posology and Method of Administration

Posology

The management of antidiabetic therapy should be individualized. The recommended dose of VYSOV-XR is 100 mg once daily. The maximum daily dose of VYSOV-XR is 100 mg.

Additional Information on Special Populations

Elderly (≥ 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). VYSOV-XR has not been evaluated in patients with moderate or severe renal impairment or with end-stage renal disease (ESRD). In such patients, immediate-release vildagliptin at the recommended dose of 50 mg once daily would be preferred.

Hepatic impairment

Vildagliptin should not be used in patients with hepatic impairment, including patients with pre-treatment alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3x the upper limit of normal (ULN).

Method of Administration

To be taken orally. VYSOV-XR can be taken with or without food. Do not break or chew the tablets.

Contraindication

VYSOV-XR is contraindicated in patients with known hypersensitivity to vildagliptin or to any of the excipients.

Special Warnings and Precautions for Use

General

VYSOV-XR is not a substitute for insulin in patients requiring insulin. VYSOV-XR should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Patients with Renal Impairment

There is no experience in patients with ESRD on hemodialysis, therefore caution needs to be exercised while using vildagliptin in these patients.

Patients with Hepatic Impairment

VYSOV-XR is not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AST >3x the upper limit of normal (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 should be performed prior to the initiation of treatment with vildagliptin in order to know the patient’s baseline value. 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 3x 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 nonclinical 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.

Drug Interactions

Vildagliptin has low potential for drug interactions with co-administered medicinal products. Since vildagliptin is not a cytochrome P (CYP) 450 enzyme substrate nor does it inhibit or induce CYP 450 enzymes, it is not likely to interact with co-medications that are substrates, inhibitors or inducers of these enzymes.

Combination with pioglitazone, metformin and glyburide

Results from studies conducted with these oral antidiabetics have shown no clinically relevant pharmacokinetic interactions.

Digoxin (Pgp 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.

Use in Special Populations

Patients with Renal Impairment

There is limited experience in patients with ESRD on hemodialysis. Therefore vildagliptin should be used with caution in these patients. 

Patients with Hepatic Impairment

VYSOV-XR is not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AST >3x the upper limit of normal (ULN).

Pregnant Women

There is insufficient experience with 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.

Lactating Women

As it is not known whether vildagliptin is excreted in human milk, Animal studies have shown excretion of vildagliptin in milk. Vildagliptin should not be used during breast-feeding.

Females and Males of Reproductive Potential

No studies on the effect on human fertility have been conducted for vildagliptin.

Pediatric Patients (below 18 years)

VYSOV-XR 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.

Geriatric Patients (65 years or above)

In patients treated with vildagliptin ≥65 years of age and ≥75 years of age, no differences were observed in the overall safety, tolerability, or efficacy between this elderly population and younger patients. However, hepatic and renal fuctions should be taken into consideration before initiating therapy with vildagliptin in this age group of patients.

Effects of 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.

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 controlled trials of at least 12 weeks duration. Of these patients, 2,264 patients received vildagliptin as monotherapy and 1,520 patients received vildagliptin in combination with another medicinal product. 2,682 patients were treated with vildagliptin 100 mg daily (either 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 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.

Rare cases of hepatic dysfunction (including hepatitis) have been reported. In these cases, the patients were generally asymptomatic without clinical sequelae and liver function tests (LFTs) returned to normal after discontinuation of treatment. In data from controlled monotherapy and add-on therapy trials up to 24 weeks in duration, the incidence of ALT or AST elevations >= 3x 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 daily, vildagliptin 50 mg twice daily and all comparators, respectively. These elevations in transaminases were generally asymptomatic, non-progressive in nature and not associated with cholestasis or jaundice.

Tabulated Summary of Adverse Drug Reactions from Clinical Trials

Adverse reactions reported in patients who received vildagliptin in double-blind studies as monotherapy and add-on therapies, are listed below, for each indication, by  system organ class and absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Monotherapy

Table 1.  Adverse reactions reported in patients who received vildagliptin 100 mg daily as monotherapy in double-blind studies (N=1,855)

Infections and infestations

Very rare

Upper respiratory tract infection

Very rare

Nasopharyngitis

Metabolism and nutrition disorders

Uncommon

Hypoglycaemia

Nervous system disorders

Common

Dizziness

Uncommon

Headache

Vascular disorders

Uncommon

Oedema peripheral

Gastrointestinal disorders

Uncommon

Constipation

Musculoskeletal and connective tissue disorders

Uncommon

Arthralgia

     

Description of selected adverse reactions

In addition, in controlled monotherapy trials with vildagliptin the overall incidence of withdrawals due to adverse reactions was no greater for patients treated with vildagliptin at a dose of 50 mg twice daily (0.3%) than for placebo (0.6%) or comparators (0.5%).

In comparative controlled monotherapy studies, hypoglycaemia was uncommon, reported in 0.4% (7 of 1,855) of patients treated with vildagliptin 50 mg twice daily compared to 0.2% (2 of 1,082) of patients in the groups treated with an active comparator or placebo, with no serious or severe events reported.

In clinical trials, weight did not change from baseline when vildagliptin 50 mg twice daily was administered as monotherapy (-0.3 kg and -1.3 kg for vildagliptin and placebo, respectively).

Clinical trials of up to 2 years’ duration did not show any additional safety signals or unforeseen risks with vildagliptin monotherapy.

Combination with Metformin

Table 2.  Adverse reactions reported in patients who received vildagliptin 100 mg daily in combination with metformin in double-blind studies (N=208)

Metabolism and nutrition disorders

Common

Hypoglycaemia

Nervous system disorders

Common

Dizziness

Common

Headache

Common

Tremor

Uncommon

Fatigue

Gastrointestinal disorders

Common

Nausea

     

Description of Selected Adverse Reactions

In clinical trials with the combination of vildagliptin + metformin,  no withdrawal due to adverse reactions was reported in either the vildagliptin 50 mg twice daily + metformin or the placebo + metformin treatment groups.

In clinical trials, the incidence of hypoglycemia was uncommon in patients receiving vildagliptin 50 mg once daily in combination with metformin (1%), patients receiving  placebo + metformin (0.4%). No severe hypoglycemic events were reported in the vildagliptin arms.

In clinical trials, weight did not change from baseline when vildagliptin 50 mg daily was added to metformin (+0.2 kg and -1.0 kg for vildagliptin and placebo, respectively).

Clinical trials of up to more than 2 years’ duration did not show any additional safety signals or unforeseen risks when vildagliptin was added on to metformin.

Combination with a Sulfonylurea

Table 3. Adverse reactions reported in patients who received vildagliptin 50 mg in combination with a sulphonylurea in double-blind studies (N=170)

Infections and infestations

Very rare

Nasopharyngitis

Metabolism and nutrition disorders

Common

Hypoglycaemia

Nervous system disorders

Common

Dizziness

Common

Headache

Common

Tremor

Common

Asthenia

Gastrointestinal disorders

Uncommon

Constipation

     

Description of Selected Adverse Reactions

In clinical trials with the combination of vildagliptin 50 mg + a sulphonylurea, the overall incidence of withdrawals due to adverse reactions was 0.6% in the vildagliptin 50 mg + sulphonylurea treatment group versus 0% in the placebo + sulphonylurea treatment group.

In clinical trials, the incidence of hypoglycemia when vildagliptin 50 mg once daily was added to glimepiride was 1.2% versus 0.6% for placebo + glimepiride. No severe hypoglycemic events were reported in the vildagliptin arms.

In clinical trials, 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)..

Combination with a Thiazolidinedione

Table 4.  Adverse reactions reported in patients who received vildagliptin 100 mg daily in combination with a thiazolidinedione in double-blind studies (N=158)

Metabolism and nutrition disorders

Common

Weight increase

Uncommon

Hypoglycaemia

Nervous system disorders

Uncommon

Headache

Uncommon

Asthenia

Gastrointestinal disorders

Common

Oedema peripheral

     

Description of Selected Adverse Reactions

In clinical trials with the combination of vildagliptin and a thiazolidinedione, no withdrawals due to adverse reactions reported in either the vildagliptin 50 mg twice daily + thiazolidinedione or the placebo + thiazolidinedione treatment groups.

In clinical trials,  the incidence of hypoglycaemia was uncommon in patients receiving vildagliptin + pioglitazone (0.6%) but common in patients receiving placebo + pioglitazone (1.9%)). No severe hypoglycemic events were reported in the vildagliptin arms.

In the pioglitazone add-on study, the absolute weight increases with placebo, Vildagliptin 100 mg daily were 1.4 and 2.7 kg, respectively.

The incidence of peripheral edema when vildagliptin was added to a maximum dose of background pioglitazone (45 mg once daily) was 7.0% compared to 2.5% for background pioglitazone alone.

Combination with Insulin

Table 5.  Adverse reactions reported in patients who received vildagliptin 100 mg daily in combination with insulin (with or without metformin) in double-blind studies (N=371)

Nervous system disorders

 

Common

Headache, Chills

Gastrointestinal disorders

 

Common

Nausea, gastroesophageal reflux disease

 

Uncommon

Diarrhea, flatulence

 Metabolism and nutrition disorders

 

Common

Decresaed blood glucose

Description of Selected Adverse Reactions

 In controlled clinical trials using vildagliptin 50 mg twice daily in combination with insulin, with or without concomitant metformin, the overall incidence of withdrawal due to adverse reactions was 0.3% in the vildagliptin treatment group and there were no cases of withdrawal in the placebo group.

The incidence of hypoglycemia was similar in both treatment groups (14.0% in the vildagliptin group versus 16.4 % in the placebo group). Two patients reported severe hypoglycemic events in the vildagliptin group, and 6 patients - in the placebo group.

At the end of the study, the effect on mean body weight was neutral (+ 0.6 kg change from baseline in the vildagliptin group and no weight change in the placebo group).

Combination with Metformin and a Sulphonylurea

Table 6.  Adverse reactions reported in patients who received vildagliptin 50 mg twice daily in combination with metformin and a sulphonylurea (N=157)

Metabolism and nutrition disorders

Common

Hypoglycaemia

Nervous system disorders

Common

Dizziness, Tremor

Skin and subcutaneous tissue disorders

Common

Hyperhidrosis

General disorders and administration site conditions

Common

Constipation

     

Description of Selected Adverse Reactions

There were no withdrawal reported due to adverse reactions in the vildagliptin + metformin + glimepiride treatment group versus. 0.6% in the placebo + metformin + glimepiride treatment group.

The incidence of hypoglycemia was common in both treatment groups (5.1% for the vildagliptin + metformin + glimepiride vs. 1.9% for the placebo + metformin + glimepiride). 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). 

Post-marketing Experience

Table 7.  Post-marketing adverse reactions

Gastrointestinal disorders

Not known

Pancreatitis

Hepatobiliary disorders

Not known

Hepatitis (reversible upon discontinuation of the medicinal product) Abnormal liver function tests (reversible upon discontinuation of the medicinal product)

Musculoskeletal and connective tissue disorders

Not known

Myalgia

Skin and subcutaneous tissue disorders

Not known

Urticaria

Exfoliative and bullous skin lesions, including bullous pemphigoid

     

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. If your patient experiences any side-effects, write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side-effects, you can help provide more information on the safety of this product.

Overdose

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 paresthesia, fever, edema and transient increase in lipase levels (2x ULN). At 600 mg, one subject experienced edema of the feet and hands, and an excessive increase in creatine phosphokinase (CPK) levels, aspartate aminotransferase (AST), C-reactive protein, and myoglobin. Three additional subjects in this dose group presented with edema of both feet, accompanied by paresthesia in two cases. All symptoms and laboratory abnormalities resolved after study drug discontinuation.

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.

Pharmacological Properties
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 Properties

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 glycemic) individuals, vildagliptin does not stimulate insulin secretion or reduce glucose levels.

By increasing endogenous GLP-1 levels, vildagliptin enhances the sensitivity of alpha cells to glucose, resulting in more glucose-appropriate glucagon secretion.

The enhanced increase in the insulin/glucagon ratio during hyperglycemia due to increased incretin hormone levels results in a decrease in fasting and postprandial hepatic glucose production, leading to reduced glycemia.

The known effect of increased GLP-1 levels to delay gastric emptying is not observed with vildagliptin treatment.

Vildagliptin sustained release tablet 100mg (once daily dosing) and reference product vildagliptin tablet 50mg (twice daily dosing) showed DPP-4 inhibition above 84% for 24.00 hours. Weighted average % DPP-4 inhibition (0.00-24.00hrs) was 85.28 with vildagliptin sustained release tablet 100mg (once daily dosing) and 86.79 with vildagliptin tablet 50mg (twice daily dosing), respectively. Thus, vildagliptin sustained release achieved primary objectives of weighted average being >80% over 24 hours.

Pharmacokinetic Properties

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 is distributed equally between plasma and red blood cells. The mean volume of distribution of vildagliptin at steady state after intravenous administration (Vss) is 71 liters, suggesting extravascular distribution.

Metabolism

Metabolism is the major elimination pathway for vildagliptin in humans, accounting for 69% of the dose. The major metabolite, LAY151, is pharmacologically inactive and is the hydrolysis product of the cyano moiety, accounting for 57% of the dose, followed by glucuronide (BQS867) and the amide hydrolysis product (4% of the 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 as shown in an in vivo study using DPP-4 deficient rats. Vildagliptin is not metabolized by cytochrome P450 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 or induce cytochrome P450 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.

Excretion

Following oral administration of - vildagliptin, approximately 85% of the dose is excreted into the urine and 15% of the dose is recovered in the feces. Renal excretion of unchanged vildagliptin accounts for 23% of the dose after oral administration. After intravenous administration to healthy subjects, the total plasma and renal clearances of vildagliptin are 41 liters/hour and 13 liters/hour, respectively. The mean elimination half-life after intravenous administration is approximately 2 hours. The elimination half-life after oral administration is approximately 3 hours.

Bioequivalence Study of Vildagliptin Sustained Release

In a randomized, open-label, two-treatment, two-period, two-sequence, single-dose, crossover study conducted in 24 healthy volunteers, it was observed that the 90% confidence intervals of the differences of least squares means between vildagliptin sustained release (once daily dosing) and conventional vildagliptin (twice daily dosing), for the Ln-transformed pharmacokinetic parameters AUC0-t and AUC0-∞ was within the bioequivalence acceptance limits of 80.00 - 125.00% (Table 8 and Figure 1).

Based on pharmacokinetic data, it is concluded that the test product vildagliptin sustained release 100 mg tablet (once daily) and the reference product (vildagliptin 50mg given twice daily), are bioequivalent.

Table 8: Geometric Least Squares Means, Ratios, 90% Confidence Intervals, ISCV and Power for Pharmacokinetic Parameters (AUC0-t) of Vildagliptin (N = 24).

 

Figure 1: Ln-Linear Plot of Mean Plasma Concentrations of Vildagliptin vs. Actual Time for Test Product (T) and Reference Product (R) (N = 24)

Special Populations

Gender

No clinically relevant differences in the pharmacokinetics of vildagliptin were observed between male and female subjects with a diverse range of age and body mass index (BMI). DPP-4 inhibition by vildagliptin was unaffected by gender. However, vildagliptin sustained release has not been studied in this patient population.

Obesity

BMI does not show any impact on the pharmacokinetic parameters of vildagliptin. DPP-4 inhibition by vildagliptin was unaffected by BMI. However, vildagliptin sustained release has not been studied in this patient population.

Hepatic Impairment

The effect of impaired hepatic function on the pharmacokinetics of vildagliptin was studied in subjects with mild, moderate, and severe hepatic impairment based on the Child-Pugh scores (ranging from 6 for mild to 12 for severe) in comparison to subjects with normal hepatic function. The exposure to vildagliptin (100 mg) after a single dose in subjects with mild and moderate hepatic impairment was decreased (20% and 8%, respectively), while the exposure to vildagliptin for subjects with severe impairment was increased by 22%. The maximum change (increase or decrease) in the exposure to vildagliptin is ~30%, which is not considered to be clinically relevant. There was no correlation between the severity of hepatic function impairment and changes in exposure to vildagliptin. However, vildagliptin sustained release has not been studied in this patient population.

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.

The AUC of vildagliptin 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. The AUC of the metabolites LAY151 increased 1.5, 3 and 7-fold and that of BQS867 increased 1.4, 2.7 and 7.3-fold in patients with mild, moderate and severe renal impairment, respectively, compared to healthy volunteers. 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 in ESRD patients were approximately 2 to 3-fold higher than in patients with severe renal impairment.

Vildagliptin was removed by hemodialysis to a limited extent (3% over a 3 to 4 hour hemodialysis session starting 4 hours post dose).

However, vildagliptin sustained release has not been studied in this patient population.

Geriatric

In  healthy elderly subjects (≥70 years), the overall exposure to vildagliptin (100 mg once daily) was increased by 32% with an 18% increase in peak plasma concentration compared to younger healthy subjects (18 to 40 years). These changes are not considered to be clinically relevant. DPP-4 inhibition by vildagliptin is not affected by age in the age groups studied.However, vildagliptin sustained release has not been studied in this patient population.

Ethnicity

Limited data suggest that race does not have any major influence on vildagliptin pharmacokinetics.However, vildagliptin sustained release has not been studied based on ethnicity.

Nonclinical Properties

Animal Toxicology and Pharmacology

Intra-cardiac impulse conduction delays were observed in dogs with a no-effect dose of 15 mg/kg (7-fold human exposure based on Cmax).

Accumulation of foamy alveolar macrophages in the lung was observed in rats and mice. The noeffect dose in rats was 25 mg/kg (5-fold human exposure based on AUC) and in mice 750 mg/kg (142-fold human exposure).

Gastrointestinal symptoms, particularly soft faeces, mucoid faeces, diarrhoea and, at higher doses, faecal blood were observed in dogs. A no-effect level was not established.

Vildagliptin was not mutagenic in conventional in vitro and in vivo tests for genotoxicity.

A fertility and early embryonic development study in rats revealed no evidence of impaired fertility, reproductive performance or early embryonic development due to vildagliptin. Embryo-foetal toxicity was evaluated in rats and rabbits. An increased incidence of wavy ribs was observed in rats in association with reduced maternal body weight parameters, with a no-effect dose of 75 mg/kg (10-fold human exposure). In rabbits, decreased foetal weight and skeletal variations indicative of developmental delays were noted only in the presence of severe maternal toxicity, with a no-effect dose of 50 mg/kg (9-fold human exposure). A pre- and postnatal development study was performed in rats. Findings were only observed in association with maternal toxicity at ≥ 150 mg/kg and included a transient decrease in body weight and reduced motor activity in the F1 generation.

A two-year carcinogenicity study was conducted in rats at oral doses up to 900 mg/kg (approximately 200 times human exposure at the maximum recommended dose). No increases in tumour incidence attributable to vildagliptin were observed. Another two-year carcinogenicity study was conducted in mice at oral doses up to 1,000 mg/kg. An increased incidence of mammary adenocarcinomas and hemangiosarcomas was observed with a no-effect dose of 500 mg/kg (59-fold human exposure) and 100 mg/kg (16-fold human exposure), respectively. The increased incidence of these tumours in mice is considered not to represent a significant risk to humans based on the lack of genotoxicity of vildagliptin and its principal metabolite, the occurrence of tumours only in one species and the high systemic exposure ratios at which tumours were observed.

In a 13-week toxicology study in cynomolgus monkeys, skin lesions have been recorded at doses ≥ 5 mg/kg/day. These were consistently located on the extremities (hands, feet, ears and tail). At 5 mg/kg/day (approximately equivalent to human AUC exposure at the 100 mg dose), only blisters were observed. They were reversible despite continued treatment and were not associated with histopathological abnormalities. Flaking skin, peeling skin, scabs and tail sores with correlating histopathological changes were noted at doses ≥ 20 mg/kg/day (approximately 3 times human AUC exposure at the 100 mg dose). Necrotic lesions of the tail were observed at ≥ 80 mg/kg/day. Skin lesions were not reversible in the monkeys treated at 160 mg/kg/day during a 4-week recovery period.

Description

VYSOV-XR, sustained release tablets contain vildagliptin, an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.

Pharmaceutical Particulars

Incompatibilities

No incompatibility studies have been found.

Shelf-Life

18 Months

Storage and Handling Instructions

Store Below 30℃ & protect from light & Moisture.

Packaging information

VYSOV-XR: 15 tablets packed in an Alu-Alu blister.

Patient Counseling Information

VYSOV-XR 100 mg tablets

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet.

What is in this leaflet

  1. What VYSOV-XR is and what it is used for
  2. What you need to know before you take VYSOV-XR
  3. How to take VYSOV-XR
  4. Possible side effects
  5. How to store VYSOV-XR
  6. Contents of the pack and other information

1. What VYSOV-XR is and what it is used for?

The active substance of VYSOV-XR, vildagliptin, belongs to a group of medicines called “oral antidiabetics”. VYSOV-XR 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 VYSOV-XR either alone or together with certain other antidiabetic medicines which you will already be taking, if these have not proved sufficiently effective to control diabetes.Type 2 diabetes develops if the body does not make enough insulin or if the insulin that the body makes does not work as well as it should. It can also develop if the body produces too much glucagon. Insulin is a substance which helps to lower the level of sugar in the blood, especially after meals.Glucagon is a substance which triggers the production of sugar by the liver, causing the blood sugar level to rise. The pancreas makes both of these substances.

How VYSOV-XR works

VYSOV-XR works by making the pancreas produce more insulin and less glucagon. This helps to control the blood sugar level. This medicine has been shown to reduce blood sugar, which may help to prevent complications from your diabetes. Even though you are now starting a medicine for your diabetes, it is important that you continue to follow the diet and/or exercise which has been recommended for you.

2. What you need to know before you take VYSOV-XR?

Do not take VYSOV-XR: if you are allergic to vildagliptin. If you think you may be allergic to vildagliptin, do not take this medicine and talk to your doctor.

Warnings and precautions

Talk to your doctor, before taking VYSOV-XR

  • If you have type 1 diabetes (i.e. your body does not produce insulin) or if you have a condition called diabetic ketoacidosis
  • If you are taking an anti-diabetic medicine known as a sulphonylurea (your doctor may want to reduce your dose of the sulphonylurea when you take it together with VYSOV-XR in order to avoid low blood glucose )
  • If you have moderate or severe kidney disease (you will need to take a lower dose of VYSOV-XR)
  • If you are on dialysis
  • If you have liver disease
  • If you suffer from heart failure
  • If you have or have had a disease of the pancreas
  • If you have previously taken vildagliptin but had to stop taking it because of liver disease, you should not take this medicine
  • Diabetic skin lesions are a common complication of diabetes. You are advised to follow the recommendations for skin and foot care that you are given by your doctor or nurse. You are also advised to pay particular attention to new onset of blisters or ulcers while taking VYSOV-XR. Should these occur, you should promptly consult your doctor. A test to determine your liver function will be performed before the start of VYSOV-XR treatment, at three-month intervals for the first year and periodically thereafter. This is so that signs of increased liver enzymes can be detected as early as possible.

Children and adolescents

The use of VYSOV-XR in children and adolescents up to 18 years of age is not recommended.

Other medicines and VYSOV-XR

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Your doctor may wish to alter your dose of VYSOV-XR if you are taking other medicines such as:

  • thiazides or other diuretics (also called water tablets)
  • corticosteroids (generally used to treat inflammation)
  • thyroid medicines
  • certain medicines affecting the nervous system

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

You should not use VYSOV-XR during pregnancy. It is not known if VYSOV-XR passes into breast milk. You should not use VYSOV-XR if you are breast-feeding or plan to breast-feed.

Driving and using machines

If you feel dizzy while taking VYSOV-XR, do not drive or use machines.

3. How to take VYSOV-XR ?

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

How much to take and when

The recommended oral dosage is one tablet once daily. The maximum daily dose is 100 mg. The tablets can be taken with or without food.

How to take VYSOV-XR

Tablet to be swallowed whole. It should not be chewed or crushed.

How long to take VYSOV-XR

  • Take VYSOV-XR every day for as long as your doctor tells you. You may have to take this treatment over a long period of time.
  • Your doctor will regularly monitor your condition to check that the treatment is having the desired effect.

If you take more VYSOV-XR than you should

If you take too many VYSOV-XR tablets, or if someone else has taken your medicine, talk to your doctor straight away. Medical attention may be needed. If you need to see a doctor or go to the hospital, take the pack with you.

If you forget to take VYSOV-XR

If you forget to take a dose of this medicine, take it as soon as you remember. Then take your next dose at the usual time. If it is almost time for your next dose, skip the dose you missed. Do not take a double dose to make up for a forgotten tablet.

If you stop taking VYSOV-XR

Do not stop taking VYSOV-XR unless your doctor tells you to. If you have questions about how long to take this medicine, talk to your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some symptoms need immediate medical attention:

You should stop taking VYSOV-XR  and see your doctor immediately if you experience the following side effects:

  • Angioedema (rare: may affect up to 1 in 1,000 people): Symptoms include swollen face, tongue or throat, difficulty swallowing, difficulties breathing, sudden onset 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-coloured 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 might reach through to your back, as well as nausea and vomiting.

Other side effects

Some patients have had the following side effects while taking vildagliptin and metformin:

  • Common (may affect up to 1 in 10 people): Trembling, headache, dizziness, nausea, low blood glucose
  • Uncommon (may affect up to 1 in 100 people): Tiredness

Some patients have had the following side effects while taking vildagliptin and a sulphonylurea:

  • Common: Trembling, headache, dizziness, weakness, low blood glucose
  • Uncommon: Constipation
  • Very rare (may affect up to 1 in 10,000 people): Sore throat, runny nose

 Some patients have had the following side effects while taking vildagliptin and a glitazone:

  • Common: Weight increase, swollen hands, ankle or feet (oedema)
  • Uncommon: Headache, weakness, low blood glucose

 Some patients have had the following side effects while taking vildagliptin alone:

  • Common: Dizziness
  • Uncommon: Headache, constipation, swollen hands, ankle or feet (oedema), joint pain, low blood glucose
  • Very rare: Sore throat, runny nose, fever

Some patients have had the following side effects while taking vildagliptin, metformin and a sulphonylurea:

  • Common: Dizziness, tremor, weakness, low blood glucose, excessive sweating

Some patients have had the following side effects while taking vildagliptin and insulin (with or without metformin):

  • Common: Headache, chills, nausea (feeling sick), low blood glucose, heartburn
  • Uncommon: Diarrhoea, flatulence
  • Since this product has been marketed, the following side effects have also been reported:
  • Frequency not known (cannot be estimated from the available data): Itchy rash, inflammation of the pancreas, localised peeling of skin or blisters, muscle pain

Reporting of side effects

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. If your patient experiences any side-effects, write to drugsafety@cipla.com. You can al so report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side-effects, you can help provide more information on the safety of this product.

5. How to store VYSOV-XR?

  • 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 the carton after “EXP”. The expiry date refers to the last day of that month.
  • Store in the original package in order to protect from moisture.
  • Do not use any VYSOV-XR pack that is damaged or shows signs of tampering.

6. Contents of the pack and other information

What VYSOV-XR contains?

The active substance is vildagliptin.

Each tablet contains 100 mg vildagliptin sustained release.

Details of Manufacturer

Synokem Pharmaceuticals Ltd.

Plot No. 56-57, Sector-6A, Integrated Industrial Estate (SIDCUL), Ranipur,

(BHEL), Haridwar-249403 (Uttarakhand).

Marketed by

CIPLA LTD.

Cipla house, Peninsula Business Park,

Ganpatrao Kadam Marg, Lower Parel,

Mumbai- 400013, India

Details of Permission or Licence Number with Date

27/UA/2018. April 19th, 2021

Date of Revision

March 2021