Applicant/ PHRC: Hetero Drugs South Africa (Pty) Ltd.

Product proprietary name: VILGLAV 50

Dosage form and strength: Each tablet contains 50 mg of vildagliptin

APPROVED PROFESSIONAL INFORMATION FOR VILGLAV

SCHEDULING STATUS

S3

1 NAME OF THE MEDICINE

VILGLAV 50 mg Tablet

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50 mg of vildagliptin.

Contains sugar lactose (30 mg per tablet)

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

White to off white, round, flat-faced, bevelled-edge tablet, approx. 8,15 mm in diameter and 3,5 ± 0,4

mm thick, debossed with ‘V15’ on one side and ‘H’ on the other side

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

VILGLAV is indicated as an adjunct to diet and exercise to improve glycaemic control in adult patients

with type 2 diabetes mellitus, as add-on therapy, in combination with metformin, a sulphonylurea

(SU), or insulin (with or without metformin) when diet, exercise and a single antidiabetic medicine do

not result in adequate glycaemic control.

VILGLAV is also indicated in triple combination with a sulphonylurea and metformin when diet and

exercise plus dual therapy with these medicines do not provide adequate glycaemic control.

Management of diabetes should always include diet control. Caloric restriction, weight loss, and

exercise are essential for the proper treatment of the diabetic patient. This is important not only for the

primary treatment of diabetes, but also as an adjunct to medicinal therapy.

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Applicant/ PHRC: Hetero Drugs South Africa (Pty) Ltd.

Product proprietary name: VILGLAV 50

Dosage form and strength: Each tablet contains 50 mg of vildagliptin

4.2 Posology and method of administration

Posology

The management of antidiabetic therapy should be individualised.

The recommended dose of VILGLAV is 50 mg a day or 50 mg twice a day in combination with

metformin or insulin (with or without metformin).

The recommended dose of VILGLAV is 50 mg twice a day for triple combination with metformin and a

SU.

When used in combination with a sulphonylurea, the recommended dose of VILGLAV is 50 mg once

daily administered in the morning. In this patient population, VILGLAV 100 mg daily was no more

effective than VILGLAV 50 mg once daily.

Special populations

Patients with renal impairment:

In patients with moderate or severe renal impairment or with End Stage Renal Disease (ESRD) on

haemodialysis the recommended dose of VILGLAV is 50 mg once daily (see section 5.2, Special

populations).

The maximum dose should be 50 mg in patients with mild renal impairment.

Elderly patients:

In patients treated with VILGLAV ≥ 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. No dosage adjustments are therefore necessary in the elderly patients without renal

impairment (see section 5.2, Special populations).

Paediatric patients:

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Applicant/ PHRC: Hetero Drugs South Africa (Pty) Ltd.

Product proprietary name: VILGLAV 50

Dosage form and strength: Each tablet contains 50 mg of vildagliptin

VILGLAV has not been studied in patients under 18 years of age: therefore, the use of VILGLAV in

paediatric patients is not recommended (see section 5.2, Special populations).

Method of administration

For oral use

VILGLAV is given orally with or without food.

4.3 Contraindications

•

VILGLAV is contraindicated in patients with known hypersensitivity to vildagliptin or to any of

the excipients of VILGLAV (see section 6.1).

•

VILGLAV is contraindicated in patients with hepatic impairment, including patients with a pre-

treatment ALT or AST > 2,5 X the upper limit of normal.

4.4 Special warnings and precautions for use

VILGLAV is not a substitute for insulin in insulin-requiring patients. VILGLAV should not be used in

patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Hepatic impairment

VILGLAV is contraindicated in patients with hepatic impairment, including patients with a pre-

treatment elevated ALT or AST (see section 4.3)

Liver enzyme monitoring

Cases of hepatic dysfunction (including hepatitis) have been reported. In these cases, the patients

were generally asymptomatic and liver function tests (LFTs) returned to normal after discontinuation

of treatment. LFTs should be performed prior to the initiation of treatment with VILGLAV.

LFT-monitoring is imperative

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Product proprietary name: VILGLAV 50

Dosage form and strength: Each tablet contains 50 mg of vildagliptin

LFTs should be monitored during VILGLAV treatment 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 to normal. Should an increase in AST or ALT of 3 X upper limit of normal or

greater persist, VILGLAV should be discontinued.

Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue

VILGLAV and contact their medical practitioner immediately. Following withdrawal of treatment with

VILGLAV and LFT normalisation, VILGLAV treatment should not be reinitiated.

Heart Failure

Vildagliptin is not recommended in patients with New York Heart Association (NYHA) Class III. Rates

of reported cardiac adverse events were higher in patients with NYHA functional class III treated with

vildagliptin than with placebo.

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.

VILGLAV may cause arthralgia that can be severe.

Renal impairment

There is limited experience in patients with ESRD on haemodialysis. Therefore VILGLAV should be

used with caution in these patients (see sections 4.2, 5.1 and 5.2).

Acute pancreatitis

Use of vildagliptin has been associated with a risk of developing acute pancreatitis. Patients should

be informed of the characteristic symptoms of acute pancreatitis.

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Product proprietary name: VILGLAV 50

Dosage form and strength: Each tablet contains 50 mg of vildagliptin

If pancreatitis is suspected, VILGLAV should be discontinued; if acute pancreatitis is confirmed,

VILGLAV 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 VILGLAV 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.

VILGLAV contains lactose. Patients with rare hereditary problems of galactose intolerance, total

lactase deficiency or glucose-galactose malabsorption should not take VILGLAV.

4.5 Interaction with other medicines and other forms of interaction

VILGLAV has a low potential for interactions. Since VILGLAV is not a cytochrome P (CYP) 450

enzyme substrate nor does it inhibit nor induces CYP 450 enzymes, it is not likely to interact with co-

medications that are substrates, inhibitors or inducers of these enzymes.

Furthermore, VILGLAV does not affect metabolic clearance of co-medications metabolised by

CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5. Interaction studies were

conducted with commonly co-prescribed medicines 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 VILGLAV.

Combination with ACE-inhibitors

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

section 4.8).

The hypoglycaemic effect of vildagliptin may be reduced by certain active substances, including

thiazides, corticosteroids, thyroid products and sympathomimetics.

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Applicant/ PHRC: Hetero Drugs South Africa (Pty) Ltd.

Product proprietary name: VILGLAV 50

Dosage form and strength: Each tablet contains 50 mg of vildagliptin

4.6 Fertility, pregnancy and lactation

Safety in pregnancy and lactation has not been established.

Pregnancy

Studies in animals have shown reproductive toxicity at high doses.

The potential risk for humans is unknown. Due to lack of human data, VILGLAV should not be used

during pregnancy.

Breastfeeding

It is unknown whether vildagliptin is excreted in human milk. Animal studies have shown excretion of

vildagliptin in milk.

Mothers on VILGLAV should not breastfeed their infants.

Fertility

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

4.7 Effects on ability to drive and use machines.

VILGLAV may cause dizziness. Patients who experience dizziness should avoid driving vehicles or

using machines.

4.8 Undesirable effects

a)

Summary of the safety profile

Cases of angioedema have been reported during treatment with VILGLAV.

Cases of hepatic dysfunction (including hepatitis) have been reported.

b)

Tabulated summary of adverse reactions

SYSTEM ORGAN

ADVERSE REACTION

Endocrine disorders

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Product proprietary name: VILGLAV 50

Dosage form and strength: Each tablet contains 50 mg of vildagliptin

Frequency unknown:

Metabolism and nutrition disorders

Frequent:

Pancreatitis

***Decreased blood glucose;

****hypoglycaemia

Nervous system disorders

Frequent:

*Tremor, *dizziness, headache; ***chills

***Gastrointestinal disorders

Frequent:

Nausea,

gastroesophageal

reflux

disease,

constipation

Less Frequent:

Diarrhoea, flatulence

Hepato-biliary disorders

Frequency unknown:

Hepatitis

****Skin and subcutaneous tissue disorders

Frequent:

Hyperhidrosis

Frequency unknown:

Urticaria, localised exfoliation or blisters

Musculoskeletal and connective tissue disorders

Frequency unknown:

Arthralgia

**General disorders and administration site conditions

Frequent:

Asthenia, peripheral oedema

*[PRODUCT NAME] in combination with metformin and sulphonylurea only

**[PRODUCT NAME] in combination with sulphonylurea only

***[PRODUCT NAME] in combination with insulin (with or without metformin)

****[PRODUCT NAME] in combination with metformin and sulphonylurea

Reporting of suspected adverse reactions

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Applicant/ PHRC: Hetero Drugs South Africa (Pty) Ltd.

Product proprietary name: VILGLAV 50

Dosage form and strength: Each tablet contains 50 mg of vildagliptin

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows

continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to

report any suspected adverse reactions via the “6.04 Adverse Drug Reactions Reporting Form”, found

online under SAHPRA’s publications: https://www.sahpra.org.za or to the Holder of certificate of

registration through the mail: pvg.cdma@heterogroups.com .

4.9 Overdose

Signs and symptoms

Muscle pain, paraesthesia, fever and oedema have been reported. Increases in lipase levels (2 x

ULN), creatine phosphokinase (CPK) levels, accompanied by elevations of aspartate

aminotransferase (AST), C- reactive protein, and myoglobin may develop.

Management:

Treatment is symptomatic and supportive.

VILGLAV is not dialysable; however, the major hydrolysis metabolite (LAY151) can be removed by

haemodialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Category and Class: A 21.2. Oral hypoglycaemics

Pharmacotherapeutic group: Drugs used in diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC

code: A10BH02

Vildagliptin is a selective dipeptidyl-peptidase-4 (DPP-4) inhibitor.

Mechanism of Action

It increases endogenous levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP

(glucose-dependent insulinotropic polypeptide) by inhibiting the enzyme responsible for their

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Product proprietary name: VILGLAV 50

Dosage form and strength: Each tablet contains 50 mg of vildagliptin

degradation, DPP-4 (dipeptidyl-peptidase-4). The incretin hormones GLP-1 and GIP enhance

glucose-dependent insulin secretion and exhibit other antihyperglycaemic actions following their

release into the circulation from the gut in response to a meal. GLP-1 also suppresses inappropriate

glucagon secretion. By increasing endogenous levels of these incretin hormones, vildagliptin

enhances glucose- dependent insulin secretion by the pancreatic β-cell and suppresses

inappropriately elevated glucagon secretion by the pancreatic α-cell.

The administration of vildagliptin results in a rapid and complete (> 90 %) inhibition of DPP-4 activity.

The duration of DPP-4 inhibition is dose-dependent. The mean residence time of DPP-4 inhibition

after 50 mg and 100 mg once-daily dosing with vildagliptin is 8,3 hours and 9,6 hours, respectively.

This inhibition in DPP-4 activity by vildagliptin is associated with increases in basal as well as meal-

stimulated GLP-1 and GIP levels throughout the day. Vildagliptin improves pancreatic islet function as

evidenced by the improved ability of the α-cell and β-cell to sense and respond to glucose.

α-cell function: An indication of α-cell function is the ability to suppress inappropriate glucagon

secretion in the presence of hyperglycaemia. In type 2 diabetes, glucagon is inappropriately

suppressed, resulting in increased hepatic glucose production. After a single oral dose of vildagliptin

(100 mg qd) in patients with type 2 diabetes glucagon levels were reduced before the evening meal,

both in the prandial period and throughout the overnight post-absorptive period relative to placebo.

β-cell function: An indication of β-cell function is glucose-dependent insulin secretion. Vildagliptin

improves pancreatic β-cell responsiveness to glucose leading to increased insulin secretion. This

effect occurs only in the presence of elevated glucose concentrations in patients with type 2 diabetes.

In non-diabetic (normal glycaemic) individuals, vildagliptin does not stimulate insulin secretion nor

does it reduce glucose levels.

First phase insulin secretion: An early and sensitive indicator of β-cell function is first phase insulin

secretion in response to intravenous glucose. In untreated type 2 diabetes patients, first phase insulin

secretion is virtually abolished, whereas patients treated with vildagliptin for 12 weeks demonstrated a

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Applicant/ PHRC: Hetero Drugs South Africa (Pty) Ltd.

Product proprietary name: VILGLAV 50

Dosage form and strength: Each tablet contains 50 mg of vildagliptin

clear improvement in restoration of first phase insulin secretion in response to a glucose stimulus.

After discontinuation of vildagliptin for 2 weeks, this improvement is diminished.

Vildagliptin inhibits hepatic glucose production during meals as well as during the overnight post-

absorptive period. Furthermore, the improvements in glycaemic control are associated with

attenuated insulin resistance.

In addition, vildagliptin reduces postprandial lipaemia reflecting an effect to decrease both

chylomicron and VLDL triglycerides.

5.2 Pharmacokinetic properties

Absorption

Following oral administration in the fasting state, vildagliptin is well absorbed with peak plasma

concentrations 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 distributes equally between

plasma and red blood cells. The mean volume of distribution of vildagliptin at steady-state after

intravenous administration (Vss) is 71 L, suggesting extravascular distribution.

Biotransformation

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

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Product proprietary name: VILGLAV 50

Dosage form and strength: Each tablet contains 50 mg of vildagliptin

using DPP-4 deficient rats. Vildagliptin is not metabolised by cytochrome P450 enzymes to any

quantifiable extent. In vitro studies demonstrated that vildagliptin does not inhibit or induce

cytochrome P450 enzymes.

Elimination

Following oral administration of [14C] - vildagliptin, approximately 85 % of the dose is excreted into

the urine and 15 % of the dose is recovered in the faeces. Renal excretion of the unchanged

vildagliptin accounts for 23 % of the dose after oral administration. After an intravenous administration

to healthy subjects, the total plasma and renal clearances of vildagliptin are 41 L/hour and 13 L/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 dose.

Linearity

Vildagliptin is well absorbed with an absolute oral 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.Special populations:

Gender

Although exposure in women was 13 % higher than in men, no statistically significant 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

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Product proprietary name: VILGLAV 50

Dosage form and strength: Each tablet contains 50 mg of vildagliptin

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 upper limit of normal (see section 4.3).

Renal impairment

In subjects with mild, moderate, and severe renal impairment, and end - stage renal disease (ESRD)

patients on haemodialysis, systemic exposure to vildagliptin was increased (Cmax 8 % - 66 %; AUC

32 % - 134 %) compared to subjects with normal renal function. Exposure to the inactive metabolite

(LAY151) increased with increasing severity of renal impairment (AUC 1,6- to 6,7-fold). Changes in

exposure to vildagliptin did not correlate with severity of renal impairment, whereas changes in

exposure to the inactive metabolite did correlate. The elimination half-life of vildagliptin was not

affected by renal impairment (see sections 4.3 and 4.2).

Elderly

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 (18-40 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.

Paediatric

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Applicant/ PHRC: Hetero Drugs South Africa (Pty) Ltd.

Product proprietary name: VILGLAV 50

Dosage form and strength: Each tablet contains 50 mg of vildagliptin

No pharmacokinetic data available.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

•

Cellulose microcrystalline

Lactose anhydrous

Magnesium stearate

Sodium starch glycolate

6.2 Incompatibilities

Not applicable

6.3 Shelf life

24 months

6.4

Special precautions for storage

•

Store at or below 25 °C.

Protect from light and moisture.

This medicine does not require any special storage conditions.

6.5 Nature and contents of container

Blister pack

Blister pack of form pack film with desiccant as a forming foil and plain Aluminium lidding foil,

containing 10 tablets per blister.

Pack size: 10 tablets per blister. 10 x 10 blisters packed in a box.

HDPE bottle

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Applicant/ PHRC: Hetero Drugs South Africa (Pty) Ltd.

Product proprietary name: VILGLAV 50

Dosage form and strength: Each tablet contains 50 mg of vildagliptin

White opaque coloured heavy weight high density polyethylene (HDPE) bottle enclosed with a white

opaque polypropylene, child resistant plastic cap with pulp liners containing molecular sieve sachet 1

g, minipax as a desiccant.

Pack size: 100 tablets per bottle.

Bulk pack

Clear transparent LDPE (Low Density Polyethylene), plain triple laminated plastic bag with open

mouth and heat-sealed bottom containing molecular sieve sachet 5 g, minipax as a desiccant.

Pack size: 1000’s

6.6 Special precautions for disposal and other handling

No special requirements

7 HOLDER OF CERTIFICATE OF REGISTRATION

Hetero Drugs South Africa (Pty) Ltd.

Waterfall Corporate Campus

Building No. 2, First floor

74 Waterfall Drive

Midrand

2066

8 REGISTRATION NUMBER(S)

56/21.1/0489

9 DATE OF FIRST AUTHORISATION

31 October 2023

10 DATE OF REVISION OF THE TEXT

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