VYSOV Tablets (Vildagliptin )

Table of Content

Type 2 diabetes mellitus (T2DM) is a group of metabolic disorders characterized by high blood glucose levels. Globally, 425 million are affected with diabetes and almost 73 million of these patients reside in India. As per ICMR-INDIAB study, around 70% of individuals with type 2 diabetes 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 is a newer oral antihyperglycaemic drug class that helps in achieving glucose control without increasing the risk of hypoglycaemia. 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 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 dual therapy as well as add-on to insulin therapy. Due to its proven safety profile, it is also considered as an effective type 2 diabetes drug choice in elderly, those with renal impairment and those who fast for long periods (such as during Ramadan).

Vildagliptin and metformin have a complementary mode of action and thus the combination is expected to provide stronger glycaemic control. Indeed, vildagliptin / metformin combination has demonstrated strong HbA1c reduction with a tolerability profile consistent with previously reported risks associated with the two drugs.

Vysov® (Vildagliptin 50 mg tablets) is indicated as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes mellitus. It is indicated as monotherapy, in dual combination (with metformin/ sulphonylurea/ thiazolidinedione), in triple combination (with metformin and sulphonylurea) as well as with insulin. The management of antihyperglycaemic therapy should be individualized. The recommended dose of Vysov® is 50 mg once or twice daily. The maximum daily dose of Vysov® is 100 mg.

Vysov-M® (Vildagliptin 50 mg + Metformin HCl 500mg/1000mg tablets) is indicated as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes mellitus inadequately controlled on metformin hydrochloride or vildagliptin alone or who are already treated with the combination of vildagliptin and metformin hydrochloride, as separate tablets. Vysov-M® is also indicated in triple combination (with metformin and sulphonylurea) and in combination with insulin. Vysov-M® is also indicated for the treatment of type 2 diabetes mellitus having HbA1c > 8% where diabetes is not adequately controlled by diet and exercise alone. The therapy needs to be individualized on the basis of effectiveness and tolerability. When using Vysov-M® do not exceed the maximum daily dose of vildagliptin (100 mg).

May 2019

For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

Qualitative and Quantitative Composition

VYSOV 50 mg

Each uncoated tablet contains:

Vildagliptin……………………50 mg

Dosage Form and Strength

Oral tablet

Clinical Particulars

Therapeutic Indication

VYSOV is indicated as an adjunct to diet and exercise to improve glycemic control           in patients with type 2 diabetes mellitus (T2DM).

  • as monotherapy
  • in dual combination
  • with metformin, when diet, exercise and metformin alone do not result in adequate glycemic control
  • with a sulfonylurea (SU), when diet, exercise and a SU alone do not result in adequate glycemic control
  • with a thiazolidinedione (TZD) when diet, exercise and a TZD do not result in adequate glycemic control
  • in triple combination
    • with a sulfonylurea and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycemic control.

VYSOV is also indicated in combination with insulin (with or without metformin) when diet, exercise and a stable dose of insulin do not result in adequate glycemic control.

VYSOV is also indicated as initial combination therapy with metformin in patients with T2DM whose diabetes is not adequately controlled by diet and exercise alone.

Posology and Method of Administration

The management of antidiabetic therapy should be individualized. The recommended dose of VYSOV is 50 mg once or twice daily. The maximum daily dose of VYSOV is 100 mg. For monotherapy, and for combination with metformin, with a thiazolidinedione or with insulin (with or without metformin), the recommended dose of VYSOV is 50 mg or 100 mg daily. When used in dual combination with a sulfonylurea, the recommended dose of VYSOV is 50 mg once daily. In this patient population, vildagliptin 100 mg daily was no more effective than vildagliptin 50 mg once daily. For triple combination with metformin and a SU, the recommended dose of VYSOV is 100 mg daily. If tighter glycemic control is required on the top of the maximum recommended daily dose of vildagliptin, the addition of other antidiabetic drugs such as metformin, an sulphonylurea, a thiazolidinedione or insulin may be considered.

For oral use. VYSOV can be administered with or without meals.

The 50 mg dose should be administered once daily in the morning. The 100 mg dose should be administered as two divided doses of 50 mg given in the morning and evening. If a dose of VYSOV is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.

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). In patients with moderate or severe renal impairment or with end-stage renal disease (ESRD), the recommended dose of VYSOV is 50 mg once daily.

Hepatic Impairment

VYSOV 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).

Pediatric Population

VYSOV is not recommended for use in children and adolescents (< 18 years). The safety and efficacy of VYSOV in children and adolescents (< 18 years) have not been established. No data are available.

Contraindication

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

Special Warnings and Precautions for Use

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

Drug Interactions

Vildagliptin has low potential for drug interactions. 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.

Furthermore, vildagliptin does not affect metabolic clearance of co-medications metabolized by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1, and CYP 3A4/5. Drug-drug interaction studies were conducted with commonly co-prescribed medications for patients with type 2 diabetes or medications with a narrow therapeutic window. As a result of these studies, no clinically relevant interactions with other oral antidiabetics (glibenclamide, pioglitazone, metformin), amlodipine, digoxin, ramipril, simvastatin, valsartan or warfarin were observed after co-administration with vildagliptin.

As with other oral antidiabetic medicinal products the hypoglycemic effect of vildagliptin may be reduced by certain active substances, including thiazides, corticosteroids, thyroid products and sympathomimetics.

Combination with ACE-inhibitors

There may be an increased risk of angioedema in patients concomitantly taking ACE-inhibitors.

Use in Special Populations

Patients with Renal Impairment

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

Patients with Hepatic Impairment

VYSOV 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 VYSOV in pregnant women. Vildagliptin was not teratogenic in either rats or rabbits. VYSOV should not be used during pregnancy unless the benefit to the mother outweighs the potential risk to the fetus.

Lactating Women

As it is not known whether vildagliptin is excreted in human milk, VYSOV should not be administered to breast-feeding women.

Females and males of reproductive potential

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

Pediatric Patients (below 18 years)

VYSOV has not been studied in patients under 18 years of age; therefore, the use of VYSOV in pediatric patients is not recommended.

Geriatric Patients (65 years or above)

In patients treated with VYSOV ≥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.

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

The safety and tolerability of vildagliptin (50 mg qd, 50 mg bid and 100 mg qd) have been assessed by pooling data from more than 11,000 patients from 36 Phase II and III studies (including 3 open label studies) ranging in duration from 12 to more than 104 weeks. The studies used in this pooled analysis have assessed vildagliptin as monotherapy, add-on therapy to other oral anti-diabetic agents (metformin, TZD, SU and insulin) and as an initial combination therapy with metformin or pioglitazone. Patients not receiving vildagliptin (all comparators group) were taking only placebo or metformin, TZD, SU, acarbose or insulin. For the calculation of frequency of adverse drug reactions for the individual indications, safety data from a subset of pivotal controlled trials of at least 12 week’s duration was considered. Safety data were obtained from 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) who received vildagliptin as monotherapy or in combination with another agent.

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 MedDRA system organ class and absolute frequency. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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).

Monotherapy

The overall incidence of withdrawal from monotherapy trials due to adverse reactions was no greater for patients treated with vildagliptin at a dose of 50 mg once daily (0.2%) or vildagliptin at a dose of 50 mg twice daily (0.1%) than for placebo (0.6%) or comparators (0.5%).

In monotherapy studies, hypoglycemia was uncommon, reported in 0.5% (2 of 409) of patients treated with vildagliptin 50 mg once daily and 0.3% (4 of 1,373) 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.

Vildagliptin is weight neutral when administered as monotherapy.

Table 1:Adverse reactions reported in patients who received vildagliptin 50 mg once daily (n=409) or 50 mg twice daily (n=1373) as monotherapy in double-blind studies

Nervous system disorders

 

Common

Dizziness

 

Uncommon

Headache

Gastrointestinal disorders

 

Uncommon

Constipation

General disorders and administration site conditions

 

Uncommon

Edema peripheral

Long term clinical trials of up to 2 years did not show any additional safety signals or unforeseen risks with vildagliptin monotherapy.

Combination with Metformin

In clinical trials with the combination of vildagliptin + metformin, 0.4% of patients withdrew due to adverse reactions in the vildagliptin 50 mg once daily + metformin treatment group, and 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 (0.9%), patients receiving vildagliptin 50 mg twice daily in combination with metformin (0.5%) and in patients receiving placebo + metformin (0.4%). No severe hypoglycemic events were reported in the vildagliptin arms.

Vildagliptin is weight neutral when administered in combination with metformin.

Table 2: Adverse reactions reported in patients who received vildagliptin 50 mg once daily (n=233) or 50 mg twice daily (n=183) in combination with metformin in double-blind studies

Nervous system disorders

 

Common

Tremor, dizziness, headache

Long-term clinical trials of up to more than 2 years did not show any additional safety signal or unforeseen risks when vildagliptin was added on to metformin.

When vildagliptin was studied as an initial combination therapy with metformin, no additional safety signal or unforeseen risk was observed.

Combination with a Sulfonylurea

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

At the recommended dose of 50 mg, vildagliptin is weight neutral when administered in combination with glimepiride.

Table 3: Adverse reactions reported in patients who received vildagliptin 50 mg once daily in combination with a sulfonylurea in double-blind studies (n=170)

Nervous system disorders

 

Common

Tremor, headache, dizziness

General disorders and administration site conditions

 

Common

Asthenia

Combination with a Thiazolidinedione

In clinical trials with the combination of vildagliptin and a thiazolidinedione, 0.7% of patients withdrew for adverse reactions in the vildagliptin 50 mg once daily + pioglitazone group, and there were no withdrawals due to adverse reactions reported in either the vildagliptin 50 mg twice daily + pioglitazone or the placebo + pioglitazone treatment groups.

In clinical trials, no hypoglycemia events were reported in patients receiving vildagliptin 50 mg once daily + pioglitazone 45 mg, hypoglycemia was uncommon in patients receiving vildagliptin 50 mg twice daily + pioglitazone 45 mg (0.6%) but common in patients receiving placebo + pioglitazone 45 mg (1.9%). No severe hypoglycemic events were reported in the vildagliptin arms.

In the pioglitazone add-on study, the change in body weight compared to placebo was +0.1 kg and +1.3 kg for vildagliptin 50 mg daily and vildagliptin 50 mg twice daily, respectively.

The incidence of peripheral edema when vildagliptin was added to a maximum dose of background pioglitazone (45 mg once daily) was 8.2% as 50 mg once daily and 7.0%, as 50 mg twice daily compared to 2.5% for background pioglitazone alone. The incidence of edema when vildagliptin was added to pioglitazone as dual initial therapy in drug naïve patients was, however, less than for pioglitazone alone (50 mg once daily 3.5%, 50 mg twice daily 6.1% vs. pioglitazone 30 mg 9.3%).

Table 4: Adverse reactions reported in patients who received vildagliptin 50 mg once daily (n= 146) or 50 mg twice daily (n=158) in combination with a thiazolidinedione in double-blind studies

Investigations

 

Common

Weight increase

General disorders and administration site conditions

 

Common

Edema peripheral

Combination with Insulin

 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).

Table 5: Adverse reactions reported in patients who received vildagliptin 50 mg twice daily in combination with insulin (with or without metformin (n=371))

Nervous system disorders

 

Common

Headache

Gastrointestinal disorders

 

Common

Nausea, gastroesophageal reflux disease

 

Uncommon

Diarrhea, flatulence

General disorders and administration site conditions

 

Common

Chills

Investigations

 

Common

Blood glucose decreased

Combination with Metformin and SU

There were no cases of 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). 

Table 6: Adverse reactions reported in patients who received vildagliptin 50 mg twice daily in combination with metformin and SU (n=157)

Nervous system disorders

 

Common

Dizziness, tremor

General disorders and administration site condition

 

Common

Asthenia

Metabolism and nutritional disorders

 

Common

Hypoglycemia

Skin and subcutaneous tissue disorders

 

Common

Hyperhidrosis

Adverse drug reactions from spontaneous reports and literature cases - Post-marketing Experience (frequency not known)

The following adverse drug reactions have been derived from post-marketing experience with vildagliptin via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency, which is therefore categorized as not known.

  • Hepatitis reversible upon drug discontinuation
  • Urticaria, bullous and exfoliative skin lesions, including bullous pemphigoid.
  • Pancreatitis.
  • Arthralgia, sometimes severe.

If you experience any side effects, talk to your doctor or pharmacist or 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

Signs and Symptoms

In healthy subjects (seven to fourteen subjects per treatment group), vildagliptin was administered in once-daily doses of 25, 50, 100, 200, 400, and 600 mg for up to 10 consecutive days. Doses up to 200 mg were well tolerated. 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, accompanied by elevations of 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

Vildagliptin is not dialyzable, however the major hydrolysis metabolite (LAY151) can be removed by hemodialysis.

Pharmacological Properties

Mechanism of Action

Vildagliptin, a member of the islet enhancer class, is a potent and selective dipeptidyl-peptidase-4 (DPP-4) inhibitor that improves glycemic control. Vildagliptin inhibition of DPP-4 results 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 50 to 100 mg daily in patients with type 2 diabetes significantly improved markers of beta cell function. The degree of improvement in beta-cell function is dependent on the initial degree of impairment; 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 reduction in inappropriate glucagon during meals in turn attenuates insulin resistance.

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. In addition, a reduction in postprandial lipemia that is not associated with vildagliptin’s incretin-mediated effect to improve islet function has been observed.

Pharmacokinetic Properties

Absorption

Following oral administration in the fasting state, vildagliptin is rapidly absorbed with an absolute bioavailability of 85%. Peak plasma concentrations for vildagliptin and the area under the plasma concentration versus time curve (AUC) increased in an approximately dose-proportional manner over the therapeutic dose range. Peak plasma concentrations for vildagliptin was observed at 1.75 hours. Co-administration with food slightly decreases the rate of absorption of vildagliptin, as characterized by a 19% decrease in peak concentrations, and a delay in the time to peak plasma concentration to 2.5 hours. There is no change in the extent of absorption, and food does not alter the overall exposure (AUC).

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 the amide hydrolysis product (4% of the dose). 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. In vitro studies demonstrated that vildagliptin does not inhibit or induce cytochrome P450 enzymes.

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 and is independent of the dose.

Special Populations

Gender

No 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.

Obesity

BMI does not show any impact on the pharmacokinetic parameters of vildagliptin. DPP-4 inhibition by vildagliptin was unaffected by BMI.

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.

The use of vildagliptin is not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AST >2.5x the ULN.

Renal Impairment

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 1.6, 3.2 and 7.3-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. Dosage adjustment may be required in patients with 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).

Geriatric

In otherwise 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.

Pediatric

No pharmacokinetic data available.

Ethnicity

There was no evidence that ethnicity affects the pharmacokinetics of vildagliptin.

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 Tablets contain vildagliptin, an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.

Pharmaceutical Particulars

Incompatibilities

Not applicable.

Shelf-Life

18 Months

Storage and Handling Instructions

Store between 8°C – 25°C. Protect from moisture.

Packaging information

VYSOV: Strip of 15 tablets

Patient Counseling Information

VYSOV 50 mg tablets

Vildagliptin

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, pharmacist or nurse.
  • 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, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

What is in this leaflet

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

1. What VYSOV is and what it is used for

The active substance of VYSOV, vildagliptin, belongs to a group of medicines called “oral antidiabetics”. VYSOV 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 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 works

VYSOV 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

Do not take VYSOV: 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, pharmacist or nurse before taking VYSOV

  • 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 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)
  • 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. Should these occur, you should promptly consult your doctor. A test to determine your liver function will be performed before the start of VYSOV 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 in children and adolescents up to 18 years of age is not recommended.

Other Medicines and VYSOV

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

Driving and using Machines

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

3. How to take VYSOV

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

How much to take and when

The amount of VYSOV people have to take varies depending on their condition. Your doctor will tell you exactly how many tablets of VYSOV to take. The maximum daily dose is 100 mg.

The usual dose of VYSOVis either:

  • 50 mg daily taken as one dose in the morning if you are taking VYSOV with another medicine called a sulphonylurea.
  • 50 mg or 100 mg daily (taken as 50 mg in the morning and 50 mg in the evening) if you are taking VYSOV alone, with another medicine called metformin or a glitazone, with a combination of metformin and a sulphonylurea, or with insulin.
  • 50 mg daily in the morning if you have moderate or severe kidney disease or if you are on dialysis.

How to take VYSOV

Swallow the tablets whole with some water.

How long to take VYSOV

  • Take VYSOV 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 than you should

If you take too many VYSOV 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

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

Do not stop taking VYSOV 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 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 VYSOV 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 VYSOV 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 VYSOV 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 VYSOV 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 VYSOV, metformin and a sulphonylurea:
  • Common: Dizziness, tremor, weakness, low blood glucose, excessive sweating
  • Some patients have had the following side effects while taking VYSOV 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

If you experience any side effects, talk to your doctor or pharmacist or 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.

5. How to store VYSOV

  • 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 pack that is damaged or shows signs of tampering.

6. Contents of the pack and other information

What VYSOV contains

The active substance is vildagliptin.

Each tablet contains 50 mg vildagliptin.

Details of Manufacturer

Mfd. By Cipla Ltd.

Registered Office :

Cipla House, Peninsula Business Park,

Ganpatrao Kadam Marg

Lower Parel

Mumbai – 400 013, India

Details of Permission or Licence Number with Date

M.L. MNB/05/109

Date of Revision

July 2020