Novartis Pharmaceuticals UK Ltd

4.       Clinical particulars

4.1     Therapeutic indications

Vildagliptin is indicated in the treatment of type 2 diabetes mellitus:

As monotherapy

-        in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance.

4.2       Posology and method of administration

Adults

When used as monotherapy or in dual combination with metformin or a thiazolidinedione, the recommended daily dose of vildagliptin is 100 mg, administered as one dose of 50 mg in the morning and one dose of 50 mg in the evening.

Paediatric population (< 18 years)

Galvus is not recommended for use in children and adolescents due to a lack of data on safety and efficacy (see also section 5.1).

Section 4.4 the paragraph relating to Cardiac failure has been amended as shown:

Experience with vildagliptin therapy in patients with congestive heart failure of New York Heart Association (NYHA) functional class I‑II is limited and therefore vildagliptin should be used cautiously in these patients. There is no experience of vildagliptin use in clinical trials in patients with NYHA functional class III‑IV and therefore use is not recommended in these patients.

A new paragraph at the end of Section 5.1 has been added as follows:

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with vildagliptin in all subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 for information on paediatric use).

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 Galvus is 50 mg once daily (see also sections 4.4, 5.1 and 5.2).

Section 4.4
Change to the wording on renal impairment

There is limited experience in patients with ESRD on haemodialysis. Therefore Galvus should be used with caution in these patients (see also section 5.2).

Section 4.8
Changes to post marketing experience regarding case of abnormal liver tests and cases of hepatitis.

During post-marketing experience the following additional adverse drug reactions have been reported:

·                Cases of abnormal liver function tests and cases of hepatitis, reversible upon discontinuation of the medicinal product, have been reported (see also section 4.4).

·                Frequency not known: urticaria, pancreatitis.

Section 5.1
Additional trial data.

A 24-week, multi-centre, randomised, double-blind, placebo-controlled trial was conducted to evaluate the treatment effect of vildagliptin 50 mg once daily compared to placebo in 515 patients with type 2 diabetes and moderate renal impairment (N=294) or severe renal impairment (N=221). 68.8% and 80.5% of the patients with moderate and severe renal impairment respectively were treated with insulin (mean daily dose of 56 units and 51.6 units respectively) at baseline. In patients with moderate renal impairment vildagliptin significantly decreased HbA_1c compared with placebo (difference of ‑0.53%) from a mean baseline of 7.9%. In patients with severe renal impairment, vildagliptin significantly decreased HbA_1c compared with placebo (difference of ‑0.56%) from a mean baseline of 7.7%.

Section 5.2
Addition of 'the glucuronide (BQS867)' in the following sentence. 

The major metabolite (LAY 151) is pharmacologically inactive and is the hydrolysis product of the cyano moiety, accounting for 57% of the dose, followed by the glucuronide (BQS867) and the amide hydrolysis products (4% of dose).

Skin disorders

Skin lesions, including blistering and ulceration have been reported in extremities of monkeys in non-clinical toxicology studies (see section 5.3). Although skin lesions were not observed at an increased incidence in clinical trials, there was limited experience in patients with diabetic skin complications. Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as blistering or ulceration, is recommended.

Pancreatitis

In post-marketing experience there have been spontaneously reported adverse reactions of acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain.

Resolution of pancreatitis has been observed after discontinuation of vildagliptin. If pancreatitis is suspected, vildagliptin and other potentially suspect medicinal products should be discontinued.

Excipients

The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

 Elderly (≥ 65 years)

No dose adjustments are necessary in elderly patients. Experience in patients aged 75 years and older is limited and caution should be exercised when treating this population (see also sections 5.1 and 5.2).

Section 4.6
4.6     Fertility, Ppregnancy and lactation

Pregnancy

There are no adequate data from the use of vildagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown. Due to lack of human data, Galvus should not be used during pregnancy.

Breast-feeding

It is not unknown whether vildagliptin is excreted in human breast milk. Animal studies have shown excretion of vildagliptin in milk. Galvus should not be used during lactation.

Section 4.8
Safety data were obtained from a total of 3,784 patients exposed to vildagliptin at a daily dose of 50mg (once daily) or 100mg (50mg twice daily or 100mg once daily) in controlled trials of at least 12 weeks duration. Of these patients, 2,264 patients received vildagliptin as monotherapy and 1,520 patients received vildagliptin in combination with another medicinal product. 2,682 patients were treated with vildagliptin 100mg daily (either 50mg twice daily or 100mg once daily) and 1,102 patients were treated with vildagliptin 50mg once daily.

The majority of adverse reactions in these trials were mild and transient, not requiring treatment discontinuations. No association was found between adverse reactions and age, ethnicity, duration of exposure or daily dose.

Rare cases of hepatic dysfunction (including hepatitis) have been reported. In these cases, the patients were generally asymptomatic without clinical sequelae and liver function returned to normal after discontinuation of treatment. In data from controlled monotherapy and add-on therapy trials of up to 24 weeks in duration, the incidence of ALT or AST elevations ³ 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 once 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.

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.

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

Combination with metformin

In controlled clinical trials with the combination of vildagliptin 100mg daily + metformin, no withdrawal due to adverse reactions was reported in either the vildagliptin 100mg daily + metformin or the placebo + metformin treatment groups.

In clinical trials, the incidence of hypoglycaemia was common in patients receiving vildagliptin 100mg daily in combination with metformin (1%) and uncommon in patients receiving placebo + metformin (0.4%). No severe hypoglycaemic events were reported in the vildagliptin arms.

In clinical trials, weight did not change from baseline when vildagliptin 100mg daily was added to metformin (+0.2 kg and ‑1.0 kg for vildagliptin and placebo, respectively).

Table 1       Adverse reactions reported in patients who received Galvus 100mg daily in combination with metformin in double-blind studies (N=208)

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

Combination with a sulphonylurea

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

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

In clinical trials, weight did not change from baseline when vildagliptin 50mg daily was added to glimepiride (‑0.1 kg and ‑0.4 kg for vildagliptin and placebo, respectively).

Table 2       Adverse reactions reported in patients who received Galvus 50mg in combination with a sulphonylurea in double-blind studies (N=170)

Combination with a thiazolidinedione

In controlled clinical trials with the combination of vildagliptin 100mg daily+ a thiazolidinedione, no withdrawal due to adverse reactions was reported in either the vildagliptin 100mg daily + thiazolidinedione or the placebo + thiazolidinedione treatment groups.

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

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

The incidence of peripheral oedema when vildagliptin 100mg daily was added to a maximum dose of background pioglitazone (45 mg once daily) was 7.0%, compared to 2.5% for background pioglitazone alone.

Table 3       Adverse reactions reported in patients who received Galvus 100mg daily in combination with a thiazolidinedione in double-blind studies (N=158)

In addition, in controlled monotherapy trials with vildagliptin the overall incidence of withdrawals due to adverse reactions was no greater for patients treated with vildagliptin at doses of 100mg daily (0.3%) than for placebo (0.6%) or comparators (0.5%).

In comparative controlled monotherapy studies, hypoglycaemia was uncommon, reported in 0.4% (7 of 1,855) of patients treated with vildagliptin 100mg daily compared to 0.2% (2 of 1,082) of patients in the groups treated with an active comparator or placebo, with no serious or severe events reported.

In clinical trials, weight did not change from baseline when vildagliptin 100mg daily was administered as monotherapy (‑0.3 kg and ‑1.3 kg for vildagliptin and placebo, respectively).

Table 4       Adverse reactions reported in patients who received Galvus 100 mg daily as monotherapy in double-blind studies (N=1,855)

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

Post-marketing experience

During post-marketing experience the following additional adverse drug reactions have been reported (frequency not known): urticaria, pancreatitis.

 
Section 10

2 July 2010

24 January 2011

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu

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

Post-marketing experience

During post-marketing experience the following additional adverse drug reaction has been reported (frequency not known): urticaria.

Update to Section 5.1 (re-wording):

More than 15,000 patients with type 2 diabetes participated in double-blind placebo- or active-controlled clinical trials of up to more than 2 years’ 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. 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.

Also to include new information:

In a clinical trial of 2 years’ duration, vildagliptin (50 mg twice daily) was compared to gliclazide (up to 320 mg/day). After two years, mean reduction in HbA_1c was ‑0.5% for vildagliptin and ‑0.6% for gliclazide, from a mean baseline HBA_1c of 8.6%. Statistical non-inferiority was not achieved. Vildagliptin was associated with fewer hypoglycaemic events (0.7%) than gliclazide (1.7%).

In a 24-week trial, vildagliptin (50 mg twice daily) was compared to pioglitazone (30 mg once daily) in patients inadequately controlled with metformin (mean daily dose: 2020 mg). Mean reductions from baseline HbA_1c of 8.4% were ‑0.9% with vildagliptin added to metformin and ‑1.0% with pioglitazone added to metformin. A mean weight gain of +1.9 kg was observed in patients receiving pioglitazone added to metformin compared to +0.3 kg in those receiving vildagliptin added to metformin.

In a clinical trial of 2 years’ duration, vildagliptin (50 mg twice daily) was compared to glimepiride (up to 6 mg/day – mean dose at 2 years: 4.6 mg) in patients treated with metformin (mean daily dose: 1894 mg). After 1 year mean reductions in HbA_1c were ‑0.4% with vildagliptin added to metformin and ‑0.5% with glimepiride added to metformin, from a mean baseline HbA_1c of 7.3%. Body weight 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 HbA_1c was similar to baseline values in both treatment groups and the body weight changes and hypoglycaemia differences were maintained.

In section 4.8 (Undesirable effects), in Table 1 and 2, Metabolism and nutrition disorders with Common – Hypoglycaemia, Added.

In section 4.8 (Undesirable effects), Table 3, Uncommon – Hypoglycaemia, Added in Metabolism and nutrition disorder section.

In section 4.8 (Undesirable effects), after table 3, first paragraph. “100mg daily” and “adverse reactions reported in patients treated with vildagliptin in excess of that in patients receiving placebo are dizziness, headache, oedema peripheral, constipation, naspharyngitis, upper respiratory tract infection and arthralgia. In these trails”  Deleted.

In section 4.8 (Undesirable effects), Table 4, Adverse reactions reported in patients who received Galvus 100mg daily as monotherapy in double-blind studies (N=1855) – Added.

In section 5.1 Pharmacodynamic properties, paragraph 8 and Table 4 labels, changed from 4 to 5.

• "and in multipacks containing 336 (3 x 112) tablets" added

SECTION 8

•   "EU/1/07/414/018" added