Consumer medicine information

Galvus [10228]

Vildagliptin

BRAND INFORMATION

Brand name

Galvus

Active ingredient

Vildagliptin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Galvus [10228].

What is in this leaflet

This leaflet answers some common questions about Galvus.

It does not contain all the available information. It does not take the place of talking to your doctor, pharmacist or diabetes educator.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. You can also download the most up to date leaflet from www.novartis.com.au.

Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will provide.

If you have any concerns about this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Galvus is used for

Galvus is used to lower blood sugar levels in patients with type 2 diabetes mellitus either alone (if you are unable to take metformin) or in combination with certain other medicines (metformin, or a sulfonylurea medicine, or pioglitazone, or metformin and a sulfonylurea, or insulin injections), when diet plus exercise plus the single or dual medicines do not provide adequate blood sugar level control.

Type 2 diabetes mellitus

Type 2 diabetes develops if the body does not produce enough insulin, or where the insulin that your 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 your blood, especially after meals. Glucagon is another substance which triggers the production of sugar by the liver, causing the blood sugar to rise. The pancreas makes both of these substances.

Galvus is a member of a class of medicines you take by mouth called DPP-4 inhibitors (dipeptidyl peptidase-4 inhibitors) that lowers blood sugar levels in patients with type 2 diabetes mellitus.

Your doctor will prescribe Galvus either alone or in combination with other antidiabetic medicines if that medicine or medicines do not sufficiently control your blood sugar level.

It is important that you continue to follow the diet and/or exercise recommended for you whilst you are on treatment with Galvus.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is only available with a doctor's prescription. It is not addictive.

There is not enough information to recommend this medicine for children.

Before you take Galvus

When you must not take it

Do not take Galvus if you have an allergy to:

  • vildagliptin (the active ingredient) or to any of the other ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath;
  • wheezing or difficulty breathing;
  • swelling of the face, lips, tongue or other parts of the body;
  • rash, itching or hives on the skin.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. In that case, return it to your pharmacist.

Before you start to take it

Tell your doctor if:

  • you have allergies to any other medicines, foods, dyes or preservatives.
    Your doctor will want to know if you are prone to allergies.
  • you are pregnant or intend to become pregnant.
    Your doctor will discuss the possible risks and benefits involved.
  • you are breast-feeding or plan to breast-feed.
    It is not known if the active ingredient of Galvus passes into breast milk and could affect your baby.
  • you have any of the following medical conditions:
    - problems with your kidneys
    - problems with your liver
    - heart failure
    - type 1 diabetes (formerly called 'juvenile onset' or 'insulin-dependent' diabetes mellitus or 'IDDM'), where the body does not produce any insulin
    - diabetic ketoacidosis, a condition where chemicals called ketones build up in the body due to very low insulin levels.

Galvus is not a substitute for insulin. You should therefore not receive Galvus for the treatment of type 1 diabetes or diabetic ketoacidosis.

If you are not sure whether any of the above conditions apply to you, your doctor can advise you.

If you have not told your doctor about any of the above, tell him/her before you take any Galvus. Your doctor will do some blood and urine tests for sugar level regularly, and for liver functions at the start of treatment and regularly while you are on treatment. Your doctor will also test your kidney function before you start treatment with Galvus.

If your doctor has told you to stop your treatment with Galvus because of liver problems, you should never start taking Galvus again.

Tell your doctor if you suffer from lactose intolerance. This is because Galvus tablets contain lactose.

Alcohol, diet, exercise and your general health all strongly affect the control of your diabetes.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop. You may need to take different amounts of your medicines or to take different medicines while you are taking Galvus. Your doctor and pharmacist have more information.

If you have not told your doctor about any of these things, tell him/her before you start taking this medicine.

How to take Galvus

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

How much to take

The usual dose is 50mg or 100mg daily. The 50mg dose should be taken as 50mg once a day (morning). The 100mg dose is taken as 50mg twice a day (in the morning and evening).

Your doctor will monitor your blood glucose levels and may increase or decrease the dose of Galvus to maintain good control of your diabetes.

Your doctor will prescribe Galvus either alone or in combination with other antidiabetic medicines, if that medicine or medicines do not sufficiently control your blood sugar level.

How to take it

Swallow Galvus tablets whole with a glass of water.

If your doctor has prescribed 100mg a day, take one 50 mg tablet in the morning and one 50 mg tablet in the evening. Do not take two tablets together at any one time.

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it. It does not matter if you take this medicine before or after food.

How long to take it

Continue taking your medicine for as long as your doctor tells you to. Your doctor will check your progress to make sure the medicine is working and will discuss with you how long your treatment should continue.

If your doctor has told you to stop your treatment with Galvus because of liver problems, you should never start taking Galvus again.

Do not stop taking Galvus unless your doctor tells you to.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone number: 13 11 26), or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have accidentally taken too much Galvus. Do this even if there are no signs of discomfort or poisoning. Keep the telephone numbers for these places handy. You may need urgent medical attention.

Symptoms of an overdose may include:

  • Swelling in hands or feet
  • Tingling or numbness in hands or feet
  • Muscle pain
  • Fever

While you are taking Galvus

Things you must do

If you become pregnant while taking this medicine, tell your doctor immediately. Galvus should not be taken if you are pregnant. Insulin is more suitable for controlling blood glucose during pregnancy.

Carefully follow your doctor's and/or dietician's advice on diet, drinking alcohol and exercise.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor will do regular checks to help prevent you from having side effects from the medicine or developing serious complications of diabetes.

Make sure you check your blood glucose levels regularly. This is the best way to tell if your diabetes is being controlled properly. Your doctor or diabetes educator will show you how and when to do this.

If you become ill or experience extra stress, injury, fever, infection or need surgery, tell your doctor. Your blood glucose may become difficult to control at these times.

Make sure you keep enough medicine to last over weekends and holidays. It is important to keep your blood glucose controlled at all times to prevent serious complications of diabetes from happening.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Galvus.

Tell any other doctor, dentist or pharmacist who treats you that you are taking Galvus.

Things you must not do

Do not give this medicine to anyone else, even if their condition seems similar to yours.

Do not use it to treat any other complaints unless your doctor tells you to.

Things to be careful of

Be careful driving, operating machinery or doing jobs that require you to be alert until you know how this medicine affects you. If your blood glucose level becomes too low, you may feel dizzy, lightheaded, weak or tired and your reaction time may be slower than usual.

If you have any of these symptoms, do not drive or do anything else that could be dangerous.

Be careful when doing any of the following things, which increase the risk of your blood glucose becoming too low:

  • drinking alcohol
  • not eating enough
  • doing unexpected or vigorous exercise

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Galvus even if you do not think it is connected with the medicine.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by these lists of possible side effects. You may not experience any of them.

Ask your doctor, pharmacist or diabetes educator to answer any questions you may have.

Tell your doctor if you notice any of the following side effects and they worry you:

  • swelling of the hands, ankles or feet
  • weakness
  • dizziness
  • headache
  • trembling
  • low blood glucose
  • nausea
  • chills
  • constipation
  • diarrhoea
  • wind (flatulence)
  • a burning sensation in the chest rising up to the throat ('heartburn')
  • weight increase
  • excessive decreased blood glucose
  • itchy rash
  • peeling of skin or blisters
  • joint pain
  • excessive sweating

Tell your doctor immediately or go to Accident and Emergency if you notice any of the following:

  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • sudden onset of rash or hives
  • yellow skin and eyes, nausea, loss of appetite, dark urine (possible symptoms of liver problems)
  • severe and persistent pain in the stomach area which might reach through your back, as well as nausea and vomiting (possible sign of inflamed pancreas)

Tell your doctor if you notice anything else that is making you feel unwell. Some people may have other side effects not yet known or mentioned in this leaflet. Some side effects (e.g. changes in liver function) can only be found by laboratory testing.

After using Galvus

Storage

  • Keep your medicine in the original container until it is time to take it.
  • Store it in a cool dry place where the temperature stays below 30°C.
  • Do not store Galvus or any other medicine in the bathroom or near a sink.
  • Do not leave it in the car or on window sills.

Keep the medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any tablets you have left over.

Product description

What it looks like

Galvus tablets are round, white to light yellowish, marked with "NVR" on one side and "FB" on the other.

Galvus tablets are available in boxes containing 14 or 60 tablets.

Ingredients

Each Galvus tablet contains 50 mg of vildagliptin as the active ingredient.

It also contains the following inactive ingredients:

  • lactose anhydrous
  • cellulose - microcrystalline
  • sodium starch glycollate
  • magnesium stearate

Galvus does not contain gluten, tartrazine or any other azo dyes.

Sponsor

Galvus is supplied in Australia by:

NOVARTIS Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
Macquarie Park NSW 2113
Telephone: 1 800 671 203
Web site: www.novartis.com.au

®= Registered Trademark

This leaflet was prepared in September 2018

Australian Registration Number:
50 mg tablet - AUST R 159561

Internal Document Code:
(gal071218c based on PI gal071218i)

Published by MIMS February 2019

BRAND INFORMATION

Brand name

Galvus

Active ingredient

Vildagliptin

Schedule

S4

 

1 Name of Medicine

The active ingredient of Galvus is vildagliptin.

6.7 Physicochemical Properties

Chemical name: 1-[(3-hydroxy-adamant-1-ylamino) acetyl]-pyrrolidine-2 (S)-carbonitrile. Molecular formula: C17H25N3O2. Molecular weight: 303.40.

Chemical structure.


CAS number.

274901-16-5.

2 Qualitative and Quantitative Composition

Vildagliptin is a white to slightly yellowish or slightly greyish crystalline powder with a melting point/ range of approximately 150°C. It is freely soluble in water.
Each Galvus tablet contains 50 mg vildagliptin, lactose anhydrous, magnesium stearate, cellulose - microcrystalline and sodium starch glycollate.
Excipients with known effect: lactose.

3 Pharmaceutical Form

Galvus (vildagliptin) is available as a 50 mg tablet.
50 mg: white to light yellowish, round flat-faced with bevelled edges, unscored tablet. One side is debossed with ''NVR" and the other side with "FB".

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group, ATC code.

Drugs used in diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC code: A10BH02.

Mechanism of action.

Vildagliptin, a member of the class that enhances islet cell insulin secretion via an augmented incretin effect, is a high affinity dipeptidyl-peptidase-4 (DPP-4) inhibitor that improves glycaemic control.
The administration of vildagliptin results in rapid and near complete inhibition of DPP-4 activity. Vildagliptin shows weak inhibition of, and rapid dissociation from DPP-8 and DPP-9, compared to DPP-4. In patients with type 2 diabetes, administration of vildagliptin led to inhibition of DPP-4 enzyme activity for a 24 hour period. 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).
The degree of improvement in beta cell function is dependent on the initial degree of impairment; in nondiabetic (normal glycaemic) 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 reduced glucagon secretion. There is a reduction in inappropriate glucagon release during meals. The increase in the insulin/ glucagon ratio with hyperglycaemia, due to increased incretin hormone levels, may thus be expected to decrease postprandial hepatic glucose production, leading to reduced glycaemia.
The known effect of increased GLP-1 levels to delay gastric emptying is not observed with vildagliptin treatment.

Clinical trials.

More than 15,000 patients with type 2 diabetes participated in double blind, placebo or active controlled clinical trials including some studies of more than 2 years of treatment duration. In these studies, vildagliptin was administered to more than 9,000 patients at daily doses of 50 mg once daily, 50 mg twice daily or 100 mg once daily. More than 5,000 male and more than 4,000 female patients received vildagliptin 50 mg once daily or 100 mg daily. More than 1,900 patients receiving vildagliptin 50 mg once daily or 100 mg daily were ≥ 65 years of age. In these trials, vildagliptin was administered as monotherapy in drug naïve patients with type 2 diabetes or in combination in patients not adequately controlled by other antidiabetic medicinal products. Monotherapy studies suggested that vildagliptin on its own had slightly less efficacy compared to sulfonylureas or pioglitazone. The role of vildagliptin in dual therapy with sulfonylureas and pioglitazone is incompletely defined. No morbidity or mortality data are available.
Overall, vildagliptin improved glycaemic control when given as monotherapy or when used in combination with metformin, a sulfonylurea, or a thiazolidinedione as measured by clinically relevant reductions in HbA1c from baseline at the study endpoint (see Table 10). Long-term extension studies with vildagliptin as add on therapy to metformin, glimepiride, or pioglitazone generally demonstrated continued glycaemic benefit at week 52. However, results were variable across studies. Therefore, the individual long-term response may vary.
In clinical trials, the magnitude of HbA1c reductions with vildagliptin was greater in patients with higher baseline HbA1c.

Monotherapy.

In a 52 week trial (study 2309), vildagliptin (50 mg twice daily) reduced baseline HbA1c by -1% compared to -1.4% for metformin (titrated to 2 g/day). Patients treated with vildagliptin reported significantly lower incidences of gastrointestinal adverse reactions versus those treated with metformin.
In a 24 week trial (study 2327), vildagliptin (50 mg twice daily) was compared to rosiglitazone (8 mg once daily). Mean reductions were -1.1% with vildagliptin and -1.3% with rosiglitazone in patients with mean baseline HbA1c of 8.7%. Patients receiving rosiglitazone experienced a mean increase in weight (+1.6 kg) while those receiving vildagliptin experienced no weight gain (-0.3 kg). The incidence of peripheral oedema was lower in the vildagliptin group than in the rosiglitazone group (2.1% vs. 4.1%, respectively).
In a long-term trial of 2 years (study 2310), vildagliptin (50 mg twice daily) was compared to gliclazide (up to 320 mg/day). After two years, mean reduction in HbA1c was -0.5% for vildagliptin and -0.6% for gliclazide. Vildagliptin had less of a weight gain (0.75 kg) and fewer hypoglycaemic events (0.7%) than gliclazide (1.6 kg and 1.7%, respectively).

Combination with metformin.

In a double blind, placebo controlled 24 week trial (study 2303; n = 544) in patients with type 2 diabetes whose hyperglycaemia was inadequately controlled on a maximal dose of metformin alone (mean metformin dose at baseline = 2100 mg/day), the addition of vildagliptin (50 mg once daily or 100 mg daily, as a divided dose of 50 mg in the morning and 50 mg in the evening) to metformin for 24 weeks led to statistically significant reductions in HbA1c and increased the proportion of patients achieving at least a 0.7% reduction in HbA1c when compared to patients who were continued on metformin plus placebo. Group mean baseline HbA1c ranged from 8.3% (placebo plus metformin) to 8.4% (in both vildagliptin plus metformin groups) (see Table 10). Vildagliptin combined with metformin resulted in additional statistically significant mean reductions in HbA1c compared to placebo (between group differences of -0.7% to -1.1% for vildagliptin 50 mg and 100 mg, respectively). The proportion of patients who achieved a decrease of ≥ 0.7% in HbA1c from baseline was statistically significantly higher in both vildagliptin plus metformin groups (46% and 60%, respectively) versus the metformin plus placebo group (20%). Patients on the combination of vildagliptin plus metformin did not experience a meaningful change in bodyweight compared to baseline. The incidence of gastrointestinal side effects ranged from 10% to 15% in the vildagliptin plus metformin groups as compared to 18% in the metformin plus placebo group. Vildagliptin added to metformin significantly reduced FPG compared to metformin plus placebo (-0.8 mmol/L for 50 mg once daily, and -1.7 mmol/L for 50 mg twice daily).
The effect of vildagliptin in combination with metformin was evaluated in another, double blind, placebo controlled add on clinical trial (study 2204E1) of 52 weeks total duration (12 week core study plus a 40 week extension) involving 132 patients with type 2 diabetes on stable doses of metformin (1,500 mg-3,000 mg daily). The addition of vildagliptin (50 mg once daily) to metformin resulted in an additional statistically significant reduction in mean HbA1c (between group difference of -0.6%) from baseline compared to placebo plus metformin (+0.1%) at the end of the 12 week study interval (mean baseline HbA1c of 7.7% and 7.9%, respectively). Of these patients, 71 continued add on treatment with vildagliptin or placebo for an additional 40 weeks (placebo controlled, double blind extension). At 52 weeks, mean change from baseline in HbA1c was statistically significantly greater and sustained with vildagliptin (50 mg) plus metformin versus patients continued on metformin plus placebo (between group difference of -1.1%).
These data indicate vildagliptin plus metformin provides a durable effect on glycaemic control over 52 weeks (see Figure 1). In contrast, glycaemic control in the metformin plus placebo group deteriorated over the course of the study.
In a double blind, active controlled 24 week trial (study 2354; n = 576), vildagliptin (100 mg/day; 50 mg in the morning and 50 mg in the evening) was compared to pioglitazone (30 mg once daily) in patients with type 2 diabetes inadequately controlled with metformin alone. Mean reductions from baseline HbA1c of 8.4% were -0.9% with vildagliptin added to metformin and -1.0% with pioglitazone added to metformin. The decrease in HbA1c from baseline > 9.0% was greater (-1.5%) in both treatment groups. Patients receiving pioglitazone in addition to metformin experienced an increase in weight of 1.9 kg while those receiving vildagliptin in addition to metformin experienced an increase in weight of 0.3 kg.
In a 28 week extension, HbA1c reductions were similar between treatment groups and the difference in bodyweight further increased.
In a long-term, double blind, active controlled trial of up to more than 2 years (study 2308; n = 3118), vildagliptin (100 mg/day; 50 mg in the morning and 50 mg in the evening) was compared to glimepiride (up to 6 mg/day) in patients with type 2 diabetes treated with metformin. After one year, mean reductions in HbA1c were -0.4% with vildagliptin added to metformin and -0.5% with glimepiride added to metformin. Bodyweight change with vildagliptin was -0.2 kg vs +1.6 kg with glimepiride. The incidence of hypoglycaemia was significantly lower in the vildagliptin group (1.7%) than in the glimepiride group (16.2%). At study endpoint (2 years), the HbA1c was similar to baseline values in both treatment groups and the bodyweight changes and the differences in hypoglycaemia were maintained.

Combination with glimepiride.

The benefit of vildagliptin as add on therapy was investigated in a double blind, placebo controlled add on trial (study 2305; n = 515), in patients with type 2 diabetes whose hyperglycaemia was inadequately controlled after switching from half maximal recommended doses of a sulfonylurea to glimepiride (4 mg). The addition of vildagliptin (50 mg once daily or 100 mg daily, as a divided dose of 50 mg in the morning and 50 mg in the evening) for 24 weeks led to additional statistically significant reductions in HbA1c from baseline versus patients continued on glimepiride plus placebo. The difference from placebo plus glimepiride was -0.64 in the 50 mg once daily group and -0.70% in the 50 mg twice daily group. Patients receiving vildagliptin in combination with glimepiride experienced either no increase in bodyweight (with vildagliptin 50 mg daily) or a slight increase (with vildagliptin 100 mg daily) relative to baseline values. Vildagliptin added to glimepiride reduced FPG compared to placebo plus glimepiride (-0.5 mmol/L for 50 mg once daily, and -0.6 mmol/L for 100 mg once daily, as divided dose of 50 mg in the morning and 50 mg in the evening).

Combination with pioglitazone.

In a double blind, placebo controlled add on trial (study 2304; n = 463) in patients with type 2 diabetes whose hyperglycaemia was inadequately controlled with prior thiazolidinedione monotherapy, patients were randomized to either continued thiazolidinedione monotherapy (pioglitazone 45 mg once daily plus placebo) or to the combination of the thiazolidinedione (pioglitazone 45 mg) plus vildagliptin (either 50 mg once daily or 50 mg twice daily) for 24 weeks. Group mean baseline HbA1c ranged from 8.6% (vildagliptin 50 mg daily plus pioglitazone) to 8.7% (vildagliptin 50 mg twice daily plus pioglitazone, or placebo plus pioglitazone).
The addition of vildagliptin led to statistically significant reductions in HbA1c and increased the proportion of patients achieving at least a 0.7% reduction in HbA1c when compared to patients who were continued on the thiazolidinedione alone. Vildagliptin combined with pioglitazone resulted in additional statistically significant mean reductions in HbA1c compared to pioglitazone plus placebo (between group differences of -0.5% to -0.7% for vildagliptin 50 mg once daily and twice daily, respectively). The proportion of patients who achieved a decrease of ≥ 0.7% in HbA1c, from baseline was statistically significantly higher in both vildagliptin plus pioglitazone groups (54% and 68%, respectively) versus the pioglitazone plus placebo group (38%). Patients on the combination experienced either no increase in bodyweight (those receiving vildagliptin 50 mg daily plus pioglitazone) or a slight increase (those receiving vildagliptin 50 mg twice daily plus pioglitazone) relative to pioglitazone plus placebo.
Vildagliptin added to pioglitazone reduced FPG compared to placebo plus pioglitazone (-0.3 mmol/L for 50 mg vildagliptin once daily, and -0.7 mmol/L for 100 mg vildagliptin once daily, as divided dose of 50 mg in the morning and 50 mg in the evening).

Combination with insulin.

A 24 week randomized, double blind, placebo controlled trial was conducted in 449 patients to evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with a stable dose of basal or premixed insulin (mean daily dose 41 U), with (N = 276) or without (N = 173) concomitant metformin. Vildagliptin in combination with insulin significantly decreased HbA1c compared with placebo: in the overall population, the placebo adjusted mean reduction from mean baseline HbA1c of 8.8% was -0.72%. In the subgroups treated with insulin with or without concomitant metformin the placebo adjusted mean reduction in HbA1c was -0.63% and -0.84%, respectively. The incidence of hypoglycaemia in the overall population was 8.4% and 7.2% in the vildagliptin and placebo groups, respectively. Changes in mean bodyweight were +0.2 kg and -0.7 kg in the vildagliptin and placebo groups, respectively.

Combination with metformin and glimepiride.

A 24 week randomized, double blind, placebo controlled study was conducted in 318 patients to evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with metformin (≥ 1,500 mg daily) and glimepiride (≥ 4 mg daily). Vildagliptin in combination with metformin and glimepiride significantly decreased HbA1c compared with placebo: the placebo adjusted mean reduction from mean baseline HbA1c 8.8% was -0.76%.

Special populations.

In a 24 week, double blind placebo controlled trial, vildagliptin (50 mg once daily) reduced HbA1c by -0.74% from a mean baseline of 7.9% in patients with moderate renal impairment and -0.88% from a mean baseline of 7.7% in patients with severe renal impairment. Reductions in patients with moderate and severe renal impairment in the placebo group were -0.21% and -0.32% respectively. The difference to placebo was statistically significant in both patient groups. In this study, 68.4% of patients with moderate renal impairment and 80.5% of patients with severe renal impairment were on background insulin therapy. At 52 weeks of treatment in the extension study, vildagliptin (50 mg once daily) reduced HbA1c by -0.57% from a mean baseline of 7.8% in patients with moderate renal impairment and -0.81% from a baseline of 7.7% in patients with severe renal impairment. Reductions in patients with moderate and severe renal impairment in the placebo group were -0.14% and -0.08% respectively. The difference to placebo was statistically significant in both patient groups.
In a 24 week double blind study comparing vildagliptin 50 mg qd to sitagliptin 25 mg qd in patients with severe renal impairment, vildagliptin reduced HbA1c by -0.54% from a mean baseline of 7.5%, while sitagliptin reduced HbA1c by -0.56% from a slightly higher baseline of 7.8%. 81.8% of patients in this study were on background insulin therapy. At 52 weeks of treatment in the extension study, the mean changes in HbA1c from baseline were also similar between the two treatments: -0.49% in the vildagliptin group (baseline 7.5%) and -0.53% in the sitagliptin group (baseline 7.8%).
A 52 week multicentre, randomized, double blind trial was conducted in patients with type 2 diabetes and congestive heart failure (CHF) New York Heart Association (NYHA) functional class I-III to evaluate the effect of vildagliptin 50 mg bid (N = 128) compared to placebo (N = 126) on left ventricular ejection fraction (LVEF). Vildagliptin was not associated with a change in left ventricular function or worsening of pre-existing CHF. Adjudicated cardiovascular events were overall balanced. There were more cardiac events in vildagliptin treated patients with NYHA class III heart failure compared to placebo. However there were imbalances in baseline CV risk favouring placebo and the number of events was low, precluding firm conclusions. Vildagliptin significantly decreased HbA1c compared with placebo (difference of 0.6%) from a mean baseline of 7.8%. In the subgroup of patients with NYHA class III heart failure, the decrease in HbA1c compared to placebo was lower (difference 0.3%) but this conclusion is limited by the small number of patients (n = 44). The incidence of hypoglycaemia in the overall population was 4.7% and 5.6% in the vildagliptin and placebo groups, respectively.
In a 24 week double blind placebo controlled trial in elderly patients ≥ 70 years, vildagliptin (50 mg once or twice daily) reduced HbA1c by -0.86% from mean baseline of 7.9% and the difference to placebo of -0.57% was statistically significant. The proportion of patients reaching the investigator defined HbA1c target at study end was higher for the vildagliptin group compared to the placebo group (52.6% vs. 27.0%, respectively) and the difference was statistically significant. The proportion of patients who experienced hypoglycaemic events was low (2.2% in the vildagliptin and 0.7% in the placebo groups), and no patients experienced severe hypoglycaemia. Vildagliptin was safe and well tolerated in the elderly patients with an overall safety profile similar to placebo.

Cardiovascular risk.

A meta-analysis of independently and prospectively adjudicated cardiovascular events from 37 phase III and phase IV monotherapy and combination therapy clinical studies of up to more than 2 years duration was performed. It involved 9,599 patients with type 2 diabetes treated with vildagliptin 50 mg once daily or 50 mg twice daily and showed that vildagliptin treatment was not associated with an increase in cardiovascular risk. The composite endpoint of adjudicated major adverse cardio-vascular events (MACE) including acute myocardial infarction, stroke or CV death was similar for vildagliptin versus combined active and placebo comparators [risk ratio (RR) 0.82 (95% confidence interval 0.61-1.11)] supporting the cardiovascular safety of vildagliptin. A MACE occurred in 83 out of 9,599 (0.86%) vildagliptin-treated patients and in 85 out of 7,102 (1.20%) comparator treated patients. Assessment of each individual MACE component showed no increased risk (similar RR). Confirmed heart failure events defined as heart failure requiring hospitalization or new onset of heart failure were reported in 41 (0.43%) vildagliptin-treated patients and 32 (0.45%) comparator-treated patients, with RR 1.08 (95% CI 0.68-1.70) showing no increased risk of heart failure in vildagliptin treated patients.

Fasting plasma glucose.

When administered as monotherapy and add on therapy, vildagliptin produced clinically relevant and consistent mean reductions from baseline in fasting plasma glucose (FPG) concentrations.

5.2 Pharmacokinetic Properties

Absorption.

Vildagliptin is rapidly 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.
Following oral administration in the fasting state, vildagliptin is rapidly absorbed with peak plasma concentrations observed at 1.75 hours. Coadministration 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 litres, 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 [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 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 litres/hour and 13 litres/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.

Geriatric patients.

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.

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.

Paediatric patients.

No pharmacokinetic data available.

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 pretreatment ALT or AST > 2.5 x the upper limit of normal (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 (see Section 4.2 Dose and Method of Administration).
Vildagliptin was removed by haemodialysis to a limited extent (3% over a 3 to 4 hour haemodialysis session starting 4 hours postdose).

Race.

There is no evidence that race affects the pharmacokinetics of vildagliptin.

5.3 Preclinical Safety Data

Genotoxicity.

Vildagliptin was not mutagenic in a bacterial reverse mutation assay and a human lymphocyte chromosomal aberration assay. Some clastogenic potential was exhibited in an in vitro micronucleus test in V79 Chinese hamster cells after long exposure to high, cytotoxic concentrations. However, no clastogenicity was observed in either mouse or rat micronucleus tests in vivo at up to ca 400 times the maximum human exposure, based on AUC. Furthermore, an in vivo mouse liver comet assay using the same dose was also negative. The weight of evidence indicates vildagliptin is unlikely to be genotoxic in humans at clinically relevant doses.

Carcinogenicity.

Long-term oral studies with vildagliptin in rats and mice showed evidence of haemangiosarcomas at high exposures. Tumour incidence was increased at exposure levels 46-235 times (mice) and 150 times (rats) human exposure at the maximum clinical dose, based on AUC. No significant increase in incidence was observed at 15 to 80 (females) times human exposure in mice. No-effect levels of ca 80 to 160 times human exposure were established in rats.
Mammary tumour incidence was increased in female mice at approximately 185 times the maximum anticipated human exposure to vildagliptin, but was not increased at ca 80 times. The tumours are thought to result from species specific hormonal disturbances.
Based on the available data vildagliptin is not anticipated to present a carcinogenic risk at clinically relevant exposures.

Effects on skin.

In a 13 week toxicology study in cynomolgus monkeys, skin lesions have been recorded at all oral doses administered (5 to 160 mg/kg/day). These were consistently located on the extremities (hands, feet, ears, scrotum and tail), and included flaking skin, peeling skin, scabs, tail sores and blisters. At 5 mg/kg/day (approximately equivalent to human AUC exposure at the 100 mg dose), lesions were reversible despite continued treatment. Necrotic lesions of the tail were observed at ≥ 80 mg/kg/day (18 times human AUC exposure at the maximum recommended clinical dose). Skin lesions were not reversible in monkeys treated at 160 mg/kg/day (35 times human AUC exposure) during a 4 week recovery period. Skin lesions have not been observed in other animal species and no excess of skin lesions with vildagliptin treatment relative to comparator treatments have been observed in the human clinical trials programme.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of diabetes mellitus type 2 in persons 18 years of age and older, as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes.
As monotherapy, in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance.
In dual combination with one of metformin, a sulfonylurea or pioglitazone when diet, exercise and the single agent do not result in adequate glycaemic control.
In triple combination with a sulfonylurea and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control.
In combination with insulin (with or without metformin) when diet, exercise and a stable dose of insulin do not result in adequate glycaemic control.

4.3 Contraindications

Hypersensitivity to vildagliptin or to any of the excipients.

4.4 Special Warnings and Precautions for Use

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

Cardiac failure.

A clinical trial of vildagliptin in patients with 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 CHF versus placebo. Clinical experience in patients with NYHA functional class III treated with vildagliptin is still limited and the results are inconclusive (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
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.

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.
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.

Other.

Vildagliptin tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose/ galactose malabsorption should not take this medicine.

Use in hepatic impairment.

Vildagliptin is not recommended in patients with hepatic impairment, including patients with a pretreatment ALT or AST > 2.5 x the 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 tests (LFTs) returned to normal after discontinuation of treatment. LFTs should be performed prior to the initiation of treatment with vildagliptin. LFTs should be monitored during vildagliptin 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 ULN or greater persist, withdrawal of therapy with vildagliptin is recommended. Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue vildagliptin and contact their physician immediately. Following withdrawal of treatment with vildagliptin and LFT normalisation, vildagliptin should not be reinitiated.

Use in renal impairment.

There is limited experience in patients with end stage renal disease (ESRD) on haemodialysis. Therefore, Galvus should be used cautiously in these patients.

Use in the elderly.

Of the 2900 patients treated with vildagliptin, 543 (18.9%) were ≥ 65 years of age and 109 (3.8%) were ≥ 75 years of age. There were no differences observed in overall safety, tolerability, or efficacy between these patients and younger patients.

Paediatric use.

The safety and effectiveness of vildagliptin in paediatric patients have not been established.

Effects on laboratory tests.

See Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment, Liver enzyme monitoring.

Arthralgia.

There have been post-marketing reports of joint pain, which may be severe, in patients taking DPP-4 inhibitors. Onset of symptoms following initiation of treatment may be rapid or may occur after longer periods. Discontinuation of therapy should be considered in patients who present with or experience an exacerbation of joint symptoms during treatment with DPP-4 inhibitors.

Bullous pemphigoid.

Post-marketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving Galvus. If bullous pemphigoid is suspected, Galvus should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Vildagliptin has low potential for drug interaction. Since vildagliptin is not a cytochrome (CYP) P450 enzyme substrate and does not inhibit or induce CYP P450 enzymes, it is not likely to interact with the concomitant medications that are substrates, inhibitors or inducers of these enzymes.
Furthermore, vildagliptin is not likely to interact with the concomitant medications that are substrates, inhibitors or inducers of CYP P450 enzymes nor does it affect metabolic clearance of comedications metabolised by CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5. Drug-drug interaction studies were conducted with the following commonly coprescribed medications for patients with type 2 diabetes or medications with a narrow therapeutic window.

Glibenclamide.

Coadministration of vildagliptin (100 mg twice daily) with glibenclamide (10 mg once daily) had no significant effect on the steady-state pharmacokinetics of vildagliptin. Vildagliptin did not alter the steady-state pharmacokinetics of glibenclamide.

Pioglitazone.

Coadministration of vildagliptin (100 mg once daily) with pioglitazone (45 mg once daily) did not alter the steady-state pharmacokinetics of vildagliptin. Vildagliptin had no effect on the steady-state pharmacokinetics of pioglitazone measured by the parent pioglitazone and its two active metabolites, MIII and MIV.

Metformin.

Coadministration of vildagliptin (100 mg once daily) with metformin (1000 mg once daily) did not alter the steady-state pharmacokinetics of metformin. Metformin (1000 mg once daily) did not affect total exposure to vildagliptin at steady state. The Cmax of vildagliptin was decreased by 18%, which is not considered to be clinically relevant.

Amlodipine.

Coadministration of vildagliptin (100 mg once daily) with amlodipine (5 mg once daily) given in combination to healthy subjects, did not alter the steady-state pharmacokinetics of amlodipine (5 mg once daily). Similarly, the steady-state pharmacokinetics of vildagliptin were unaffected by coadministration of amlodipine.

Valsartan.

Coadministration of vildagliptin (100 mg once daily) with valsartan (320 mg once daily) did not alter the steady-state pharmacokinetics of vildagliptin. Coadministration of vildagliptin with valsartan resulted in an increased exposure to valsartan (AUC by 24% and Cmax by 14%). However, these changes are not considered to be clinically relevant.

Ramipril.

Coadministration of vildagliptin (100 mg once daily) with ramipril (5 mg once daily) to healthy subjects, did not alter the steady-state pharmacokinetics of ramipril and its active metabolite, ramiprilat. Similarly, ramipril did not affect the steady-state pharmacokinetics of vildagliptin.

Simvastatin.

Coadministration of vildagliptin (100 mg once daily) with simvastatin (80 mg once daily) did not alter the steady-state pharmacokinetics of simvastatin and its active metabolite, simvastatin hydroxyacid. Similarly, simvastatin did not influence the steady-state pharmacokinetics of vildagliptin.

Digoxin.

Coadministration of vildagliptin (100 mg once daily) with digoxin (0.5 mg loading dose on day 1 and a 0.25 mg maintenance dose from day 2 to day 7) did not affect the pharmacokinetics of digoxin at steady state, and digoxin did not alter the pharmacokinetics of vildagliptin.

Warfarin.

Coadministration of vildagliptin (100 mg once daily) with warfarin (25 mg single dose) did not alter the pharmacokinetics of warfarin and warfarin did not influence the pharmacokinetics of vildagliptin (100 mg once daily). Coadministration of vildagliptin did not affect the pharmacodynamic parameters of prothrombin times such as AUCPT, PTmax, AUCINR, INRmax following administration of warfarin 25 mg in comparison with coadministration of placebo.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No studies on the effect on human fertility have been conducted for Galvus. Vildagliptin did not impair male or female fertility or early embryonic development in rats at oral doses corresponding to 160 times human exposure at the maximum clinical dose.
(Category B3)
Vildagliptin was not teratogenic in either rats or rabbits at exposures up to ca 115 times and 40 times the maximum expected human exposure, respectively. A slight treatment related increase in the incidence of fetal rib abnormalities was observed in the fetuses of rats at oral doses of 225 mg/kg/day (approximately 30 times the human AUC exposure at the 100 mg dose). There is insufficient experience with Galvus in pregnant women. Vildagliptin should not be used during pregnancy unless the benefit to the mother outweighs the potential risk to the foetus. Attainment of strict normoglycaemia during pregnancy may require conversion to insulin monotherapy.
Vildagliptin is excreted in the milk of lactating rats. As it is not known whether vildagliptin is excreted in human milk, vildagliptin should not be administered to a breastfeeding mother.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.
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 11,500 patients from 38 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 antidiabetic 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 weeks 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, gender, 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 ≥ 3 x 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, nonprogressive in nature and not associated with cholestasis or jaundice.
Adverse reactions reported in patients who received vildagliptin in double blind studies as monotherapy and add on therapy 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, hypoglycaemia was uncommon, reported in 0.5% (2 of 409) of patients treated with vildagliptin 50 mg once daily and 0.3% (4 of 1373) 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. See Table 1.
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 plus metformin, 0.4% of patients withdrew due to adverse reactions in the vildagliptin 50 mg once daily plus metformin, and no withdrawal due to adverse reactions was reported in either the vildagliptin 50 mg bid plus metformin or the placebo plus metformin treatment groups.
In clinical trials, the incidence of hypoglycaemia 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 plus metformin (0.4%). No severe hypoglycaemic events were reported in the vildagliptin arms.
Vildagliptin is weight neutral when administered in combination with metformin. See Table 2.
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.

Combination with glimepiride.

In clinical trials with the combination of vildagliptin 50 mg plus glimepiride, the overall incidence of withdrawals due to adverse reactions was 0.6% in the vildagliptin 50 mg plus glimepiride vs 0% in the placebo plus glimepiride treatment group.
In clinical trials, the incidence of hypoglycaemia when vildagliptin 50 mg once daily was added to glimepiride was 1.2% versus 0.6% for placebo plus glimepiride. No severe hypoglycaemic 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). See Table 3.

Combination with pioglitazone.

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 plus pioglitazone group, and there were no withdrawals due to adverse reactions reported in either the vildagliptin 50 mg twice daily plus pioglitazone or the placebo plus pioglitazone treatment groups.
In clinical trials, no hypoglycaemia events were reported in patients receiving vildagliptin 50 mg once daily plus pioglitazone 45 mg, hypoglycaemia was uncommon in patients receiving vildagliptin 50 mg twice daily plus pioglitazone 45 mg (0.6%) but common in patients receiving placebo plus pioglitazone 45 mg (1.9%). No severe hypoglycaemic events were reported in the vildagliptin arms.
In the pioglitazone add on study, the change in bodyweight 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 oedema 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 oedema 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%). See Table 4.

Combination with insulin.

Pooled safety data from two controlled clinical trials using vildagliptin 50 mg twice daily in combination with insulin, with or without concomitant metformin, identified the following adverse reactions.

Common.

Headache, nausea, gastroesophageal reflux disease, chills, blood glucose decreased.

Uncommon.

Diarrhoea, flatulence.
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 hypoglycaemia was similar in both treatment groups (14.0% in the vildagliptin group vs 16.4% in the placebo group). Two patients reported severe hypoglycaemic events in the vildagliptin group, and 6 patients in the placebo group.
At the end of the study, the effect on mean bodyweight was neutral (+0.6 kg change from baseline in the vildagliptin group and no weight change in the placebo group).
The adverse effect profiles for the vildagliptin and placebo groups from the 24 week study investigating vildagliptin as add on to insulin treatment (with or without metformin) is shown in Table 5.

Combination with metformin and a sulfonylurea.

There were no cases of withdrawal reported due to adverse reactions in the vildagliptin + metformin + glimepiride treatment group vs 0.6% in the placebo + metformin + glimepiride treatment group.
The incidence of hypoglycaemia was common (≥ 1/100, < 1/10) in both treatment groups, but was numerically greater for the vildagliptin + metformin + glimepiride group (5.1%) than the placebo + metformin + glimepiride group (1.9%). One severe hypoglycaemic event was reported in the vildagliptin group.
At the end of the study, the effect on mean bodyweight was neutral (+0.6 kg in the vildagliptin group and -0.1 kg in the placebo group). See Table 6.

Special populations.

The adverse effect profiles for the vildagliptin and placebo groups from the 24 week core study and the 28 week extension study in patients with type 2 diabetes and moderate or severe renal insufficiency are shown in Table 7 and Table 8.
The adverse effect profiles for the vildagliptin and sitagliptin groups of the 24 week core study and 28 week extension study investigating patients with type 2 diabetes and severe renal insufficiency are shown in Table 9.

Postmarketing experience: adverse drug reactions from spontaneous reports and literature cases (frequency not known).

The following adverse drug reactions have been derived from postmarketing experience with Galvus 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 (see Section 4.4 Special Warnings and Precautions for Use).
Urticaria, bullous and exfoliative skin lesions, including bullous pemphigoid (see Section 4.4 Special Warnings and Precautions for Use).
Pancreatitis.
Arthralgia, sometimes severe.

4.2 Dose and Method of Administration

The management of antidiabetic therapy should be individualised.
Doses greater than 100 mg are not recommended.
Vildagliptin can be administered orally with or without a meal.
The 50 mg dose should be administered once daily in the morning. The 100 mg daily dose should be administered as two divided doses of 50 mg taken in the morning and evening.
If a dose of Galvus is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.

As monotherapy.

The recommended dose of Galvus is 50 mg twice daily (100 mg daily dose) for monotherapy.

In dual combination therapy.

When used in dual combination with metformin or a thiazolidinedione (clinical experience is with pioglitazone as dual therapy), the recommended dose of vildagliptin is 50 mg once daily or 100 mg (50 mg twice) daily.
When used in dual combination with a sulfonylurea (clinical experience is with glimepiride as dual therapy), the recommended dose of vildagliptin is 50 mg once daily administered in the morning. In this patient population, vildagliptin 100 mg daily was no more effective than vildagliptin 50 mg once daily and was associated with a higher rate of hypoglycaemia than the 50 mg dose.

In combination with insulin.

The recommended dose of Galvus is 50 mg once daily or 100 mg (50 mg twice) daily in combination with insulin (with or without metformin).

In triple combination therapy.

The recommended dose of Galvus is 100 mg daily (50 mg twice a day) for triple combination with metformin and a sulfonylurea.

Patients with hepatic impairment.

Vildagliptin is not recommended in patients with hepatic impairment including patients with a pretreatment ALT or AST > 2.5 x the ULN.

Patients with renal impairment.

Glomerular filtration rate (GFR) is to be estimated prior to commencement of therapy.
No dosage adjustment of vildagliptin is required in patients with mild chronic kidney disease (eGFR 60-89 mL/min/1.73 m2). In patients with moderate (eGFR 30-59 mL/min/1.73 m2) or severe (eGFR 15-29 mL/min/1.73 m2) renal impairment or end stage renal disease (ESRD), the recommended dose of vildagliptin is 50 mg once daily (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment; Section 5.1 Pharmacodynamic Properties, Clinical trials and Section 5.2 Pharmacokinetic Properties, Special populations).

Elderly patients.

In patients ≥ 65 years of age and ≥ 75 years of age treated with vildagliptin, no differences were observed in the overall safety, tolerability, or efficacy between this elderly population and younger patients. However, renal function typically declines in elderly patients which increases overall exposure and peak plasma concentration of vildagliptin. No dosage adjustments are necessary in the elderly patients with mild renal impairment. For elderly patients with moderate or severe renal impairment, or end stage renal disease, similar dosing adjustment should be followed as for younger patients (See Section 5.2 Pharmacokinetic Properties, Special populations and Section 4.2 Dose and Method of Administration, Patients with renal impairment).

Paediatric patients.

Vildagliptin has not been studied in patients under 18 years of age; therefore, the use of vildagliptin in paediatric patients is not recommended (see Section 5.2 Pharmacokinetic Properties, Special populations).

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Patients who may experience dizziness should therefore avoid driving vehicles or using machines.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
In healthy subjects (seven to fourteen subjects per treatment group), Galvus (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 600 mg, one subject experienced oedema 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 oedema of both feet, accompanied by paraesthesia in two cases. At 400 mg, there were three cases of muscle pain, and individual cases of mild and transient paraesthesia, fever, oedema and transient increase in lipase levels (twice the ULN). All adverse events and laboratory abnormalities resolved after study drug discontinuation.
Galvus is not dialysable, however the major hydrolysis metabolite (LAY151) can be removed by haemodialysis.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Protect from moisture.

6.5 Nature and Contents of Container

Galvus is available in blister packs containing 14, 60 or 112 tablets.
*Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes