ANNEX I
`
`SUMMARY OF PRODUCT CHARACTERISTICS
`
`1
`
`
`
`AstraZeneca Exhibit 2080
`Mylan v. AstraZeneca
`IPR2015-01340
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`Page 1 of 36
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`NAME OF THE MEDICINAL PRODUCT
`
`1.
`
`Galvus 50 mg tablets
`
`
`
`QUALITATIVE AND QUANTITATIVE COMPOSITION
`
`2.
`
`Each tablet contains 50 mg of vildagliptin.
`
`Excipient with known effect: Each tablet contains 47.82 mg lactose (anhydrous).
`
`For the full list of excipients, see section 6.1.
`
`
`
`PHARMACEUTICAL FORM
`
`3.
`
`Tablet.
`
`White to light yellowish, round (8 mm diameter), flat-faced, bevelled-edge tablet. One side is
`debossed with “NVR”, and the other side with “FB”.
`
`
`
`CLINICAL PARTICULARS
`
`4.
`
`4.1 Therapeutic indications
`
`Vildagliptin is indicated in the treatment of type 2 diabetes mellitus in adults:
`
`As monotherapy
`-
`in patients inadequately controlled by diet and exercise alone and for whom metformin is
`inappropriate due to contraindications or intolerance.
`
`-
`
`
`As dual oral therapy in combination with
`-
`metformin, in patients with insufficient glycaemic control despite maximal tolerated dose of
`monotherapy with metformin,
`a sulphonylurea, in patients with insufficient glycaemic control despite maximal tolerated dose
`of a sulphonylurea and for whom metformin is inappropriate due to contraindications or
`intolerance,
`a thiazolidinedione, in patients with insufficient glycaemic control and for whom the use of a
`thiazolidinedione is appropriate.
`
`-
`
`
`As triple oral therapy in combination with
`-
`a sulphonylurea and metformin when diet and exercise plus dual therapy with these medicinal
`products do not provide adequate glycaemic control.
`
`
`Vildagliptin is also indicated for use in combination with insulin (with or without metformin) when
`diet and exercise plus a stable dose of insulin do not provide adequate glycaemic control.
`
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`2
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`Page 2 of 36
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`4.2 Posology and method of administration
`
`Posology
`Adults
`When used as monotherapy, in combination with metformin, in combination with thiazolidinedione,
`in combination with metformin and a sulphonylurea, or in combination with insulin (with or without
`metformin), 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.
`
`When used in dual combination with a sulphonylurea, 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.
`
`When used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be
`considered to reduce the risk of hypoglycaemia.
`
`Doses higher than 100 mg are not recommended.
`
`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.
`
`
`The safety and efficacy of vildagliptin as triple oral therapy in combination with metformin
`
`and a thiazolidinedione have not been established.
`
`
`Additional information on special populations
`Elderly (≥ 65 years)
`No dose adjustments are necessary in elderly patients (see also sections 5.1 and 5.2).
`
`Renal impairment
`No dose adjustment is required in patients with mild renal impairment (creatinine clearance
`≥ 50 ml/min). In patients with moderate or severe renal impairment or with end-stage renal disease
`(ESRD), the recommended dose of Galvus is 50 mg once daily (see also sections 4.4, 5.1 and 5.2).
`
`Hepatic impairment
`Galvus should not be used in patients with hepatic impairment, including patients with pre-treatment
`alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3x the upper limit of normal
`(ULN) (see also sections 4.4 and 5.2).
`
`Paediatric population
`Galvus is not recommended for use in children and adolescents (< 18 years). The safety and efficacy
`of Galvus in children and adolescents (< 18 years) have not been established. No data are available
`(see also section 5.1).
`
`
`Method of administration
`
`Oral use
`
`Galvus can be administered with or without a meal (see also section 5.2).
`
`
`4.3 Contraindications
`
`Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
`
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`4.4 Special warnings and precautions for use
`
`General
`Galvus is not a substitute for insulin in insulin-requiring patients. Galvus should not be used in
`patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
`
`Renal impairment
`There is limited experience in patients with ESRD on haemodialysis. Therefore Galvus should be
`used with caution in these patients (see also sections 4.2, 5.1 and 5.2).
`
`Hepatic impairment
`Galvus should not be used in patients with hepatic impairment, including patients with pre-treatment
`ALT or AST > 3x ULN (see also sections 4.2 and 5.2).
`
`Liver enzyme monitoring
`Rare cases of hepatic dysfunction (including hepatitis) have been reported. In these cases, the patients
`were generally asymptomatic without clinical sequelae and liver function test results returned to
`normal after discontinuation of treatment. Liver function tests should be performed prior to the
`initiation of treatment with Galvus in order to know the patient’s baseline value. Liver function
`should be monitored during treatment with Galvus at three-month intervals during the first year and
`periodically thereafter. Patients who develop increased transaminase levels should be monitored with
`a second liver function evaluation to confirm the finding and be followed thereafter with frequent
`liver function tests until the abnormality(ies) return(s) to normal. Should an increase in AST or ALT
`of 3x ULN or greater persist, withdrawal of Galvus therapy is recommended.
`
`Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue
`Galvus.
`
`Following withdrawal of treatment with Galvus and LFT normalisation, treatment with Galvus should
`not be reinitiated.
`
`Cardiac failure
`A clinical trial of vildagliptin in patients with New York Heart Association (NYHA) functional
`class I-III showed that treatment with vildagliptin was not associated with a change in left-ventricular
`function or worsening of pre-existing congestive heart failure (CHF) versus placebo. Clinical
`experience in patients with NYHA functional class III treated with vildagliptin is still limited and
`results are inconclusive (see section 5.1).
`
`There is no experience of vildagliptin use in clinical trials in patients with NYHA functional class IV
`and therefore use is not recommended in these patients.
`
`Skin disorders
`Skin lesions, including blistering and ulceration have been reported in extremities of monkeys in 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.
`Furthermore, there have been post-marketing reports of bullous and exfoliative skin lesions.
`Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as
`blistering or ulceration, is recommended.
`
`Acute pancreatitis
`Use of vildagliptin has been associated with a risk of developing acute pancreatitis. Patients should be
`informed of the characteristic symptom of acute pancreatitis.
`
`If pancreatitis is suspected, vildagliptin should be discontinued; if acute pancreatitis is confirmed,
`vildagliptin should not be restarted. Caution should be exercised in patients with a history of acute
`pancreatitis.
`
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`Interaction with other medicinal products and other forms of interaction
`
`
`Hypoglycaemia
`Sulphonylureas are known to cause hypoglycaemia. Patients receiving vildagliptin in combination
`with a sulphonylurea may be at risk for hypoglycaemia. Therefore, a lower dose of sulphonylurea may
`be considered to reduce the risk of hypoglycaemia.
`
`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.
`
`4.5
`
`Vildagliptin has a low potential for interactions with co-administered medicinal products. Since
`vildagliptin is not a cytochrome P (CYP) 450 enzyme substrate and does not inhibit or induce CYP
`450 enzymes, it is not likely to interact with active substances that are substrates, inhibitors or
`inducers of these enzymes.
`
`Combination with pioglitazone, metformin and glyburide
`Results from studies conducted with these oral antidiabetics have shown no clinically relevant
`pharmacokinetic interactions.
`
`Digoxin (Pgp substrate), warfarin (CYP2C9 substrate)
`Clinical studies performed with healthy subjects have shown no clinically relevant pharmacokinetic
`interactions. However, this has not been established in the target population.
`
`Combination with amlodipine, ramipril, valsartan or simvastatin
`Drug-drug interaction studies in healthy subjects were conducted with amlodipine, ramipril, valsartan
`and simvastatin. In these studies, no clinically relevant pharmacokinetic interactions were observed
`after co-administration with vildagliptin.
`
`As with other oral antidiabetic medicinal products the hypoglycaemic effect of vildagliptin may be
`reduced by certain active substances, including thiazides, corticosteroids, thyroid products and
`sympathomimetics.
`
`4.6 Fertility, pregnancy 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 unknown whether vildagliptin is excreted in human milk. Animal studies have shown excretion of
`vildagliptin in milk. Galvus should not be used during breast-feeding.
`
`Fertility
`No studies on the effect on human fertility have been conducted for Galvus (see section 5.3).
`
`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
`experience dizziness as an adverse reaction should avoid driving vehicles or using machines.
`
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`5
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`4.8 Undesirable effects
`
`Summary of the safety profile
`Safety data were obtained from a total of 3,784 patients exposed to vildagliptin at a daily dose of
`50 mg (once daily) or 100 mg (50 mg twice daily or 100 mg once daily) in controlled trials of at least
`12 weeks duration. Of these patients, 2,264 patients received vildagliptin as monotherapy and
`1,520 patients received vildagliptin in combination with another medicinal product. 2,682 patients
`were treated with vildagliptin 100 mg daily (either 50 mg twice daily or 100 mg once daily) and
`1,102 patients were treated with vildagliptin 50 mg once daily.
`
`The majority of adverse reactions in these trials were mild and transient, not requiring treatment
`discontinuations. No association was found between adverse reactions and age, ethnicity, duration of
`exposure or daily dose.
`
`Rare cases of 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  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.
`
`Tabulated list of adverse reactions
`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, adverse reactions are presented
`in order of decreasing seriousness.
`
`Combination with metformin
`
`Table 1
`
`Adverse reactions reported in patients who received Galvus 100 mg daily in
`combination with metformin in double-blind studies (N=208)
`
`
`
`
`
`Metabolism and nutrition disorders
`
`Common
`Hypoglycaemia
`Nervous system disorders
`
`Common
`
`Common
`
`Common
`
`Uncommon
`Gastrointestinal disorders
`
`Common
`
`Tremor
`Headache
`Dizziness
`Fatigue
`
`Nausea
`
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`Description of selected adverse reactions
`In controlled clinical trials with the combination of vildagliptin 100 mg daily + metformin, no
`withdrawal due to adverse reactions was reported in either the vildagliptin 100 mg daily + metformin
`or the placebo + metformin treatment groups.
`
`In clinical trials, the incidence of hypoglycaemia was common in patients receiving vildagliptin
`100 mg 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 100 mg daily was added to
`metformin (+0.2 kg and -1.0 kg for vildagliptin and placebo, respectively).
`
`Clinical trials of up to more than 2 years’ duration did not show any additional safety signals or
`unforeseen risks when vildagliptin was added on to metformin.
`
`Combination with a sulphonylurea
`
`Table 2
`
`Adverse reactions reported in patients who received Galvus 50 mg in combination
`with a sulphonylurea in double-blind studies (N=170)
`
`
`
`Infections and infestations
`Nasopharyngitis
`
`Very rare
`Metabolism and nutrition disorders
`
`Common
`Hypoglycaemia
`Nervous system disorders
`
`Common
`
`Common
`
`Common
`
`Common
`Gastrointestinal disorders
`
`Uncommon
`
`Tremor
`Headache
`Dizziness
`Asthenia
`
`Constipation
`
`
`Description of selected adverse reactions
`In controlled clinical trials with the combination of vildagliptin 50 mg + a sulphonylurea, the overall
`incidence of withdrawals due to adverse reactions was 0.6% in the vildagliptin 50 mg + sulphonylurea
`vs 0% in the placebo + sulphonylurea 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 + 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).
`
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`Combination with a thiazolidinedione
`
`Table 3
`
`Adverse reactions reported in patients who received Galvus 100 mg daily in
`combination with a thiazolidinedione in double-blind studies (N=158)
`
`
`
`Metabolism and nutrition disorders
`
`Common
`Weight increase
`
`Uncommon
`Hypoglycaemia
`Nervous system disorders
`
`Uncommon
`
`Uncommon
`Vascular disorders
`
`Common
`
`Headache
`Asthenia
`
`Oedema peripheral
`
`
`Description of selected adverse reactions
`In controlled clinical trials with the combination of vildagliptin 100 mg daily+ a thiazolidinedione, no
`withdrawal due to adverse reactions was reported in either the vildagliptin 100 mg 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 100 mg daily
`were 1.4 and 2.7 kg, respectively.
`
`The incidence of peripheral oedema when vildagliptin 100 mg 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.
`
`Monotherapy
`
`Table 4
`
`Adverse reactions reported in patients who received Galvus 100 mg daily as
`monotherapy in double-blind studies (N=1,855)
`
`
`
`Infections and infestations
`
`Very rare
`Upper respiratory tract infection
`
`Very rare
`Nasopharyngitis
`Metabolism and nutrition disorders
`
`Uncommon
`Hypoglycaemia
`Nervous system disorders
`
`Common
`
`Uncommon
`Vascular disorders
`
`Uncommon
`Gastrointestinal disorders
`Constipation
`
`Uncommon
`Musculoskeletal and connective tissue disorders
`
`Uncommon
`Arthralgia
`
`Dizziness
`Headache
`
`Oedema peripheral
`
`
`Description of selected adverse reactions
`In addition, in controlled monotherapy trials with vildagliptin the overall incidence of withdrawals
`due to adverse reactions was no greater for patients treated with vildagliptin at doses of 100 mg daily
`(0.3%) than for placebo (0.6%) or comparators (0.5%).
`
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`In comparative controlled monotherapy studies, hypoglycaemia was uncommon, reported in 0.4% (7
`of 1,855) of patients treated with vildagliptin 100 mg 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 100 mg daily was
`administered as monotherapy (-0.3 kg and -1.3 kg for vildagliptin and placebo, respectively).
`
`Clinical trials of up to 2 years’ duration did not show any additional safety signals or unforeseen risks
`with vildagliptin monotherapy.
`
`Combination with metformin and a sulphonylurea
`
`Table 5
`
`Adverse reactions reported in patients who received Galvus 50 mg twice daily in
`combination with metformin and a sulphonylurea (N=157)
`
`
`
`Metabolism and nutritional disorders
`
`Common
`Hypoglycaemia
`Nervous system disorders
`Dizziness, tremor
`
`Common
`Skin and subcutaneous tissue disorders
`
`Common
`Hyperhidrosis
`General disorders and administration site conditions
`
`Common
`Asthenia
`
`
`Description of selected adverse reactions
`There were no withdrawals due to adverse reactions reported in the vildagliptin + metformin +
`glimepiride treatment group versus 0.6% in the placebo + metformin + glimepiride treatment group.
`
`The incidence of hypoglycaemia was common in both treatment groups (5.1% for the vildagliptin +
`metformin + glimepiride group versus 1.9% for the placebo + metformin + glimepiride group). One
`severe hypoglycaemic event was reported in the vildagliptin group.
`
`At the end of the study, effect on mean body weight was neutral (+0.6 kg in the vildagliptin group and
`-0.1 kg in the placebo group).
`
`Combination with insulin
`
`Table 6
`
`Adverse reactions reported in patients who received Galvus 100 mg daily in
`combination with insulin (with or without metformin) in double-blind studies
`(N=371)
`
`
`Metabolism and nutrition disorders
`Common
`Decreased blood glucose
`
`Nervous system disorders
`Common
`
`Gastrointestinal disorders
`Common
`
`Uncommon
`
`
`
`Headache, chills
`
`Nausea, gastro-oesophageal reflux disease
`Diarrhoea, flatulence
`
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`Description of selected adverse reactions
`In controlled clinical trials using vildagliptin 50 mg twice daily in combination with insulin, with or
`without concomitant metformin, the overall incidence of withdrawals due to adverse reactions was
`0.3% in the vildagliptin treatment group and there were no withdrawals 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, effect on mean body weight was neutral (+0.6 kg change from baseline in the
`vildagliptin group and no weight change in the placebo group).
`
`Post-marketing experience
`
`Table 7
`
`
`Post-marketing adverse reactions
`
`Gastrointestinal disorders
`
`Not known
`Hepatobiliary disorders
`
`Not known
`
`Pancreatitis
`
`Hepatitis (reversible upon discontinuation of the medicinal product)
`Abnormal liver function tests (reversible upon discontinuation of the
`medicinal product)
`Musculoskeletal and connective tissue disorders
`
`Not known
`Myalgia
`Skin and subcutaneous tissue disorders
`
`Not known
`Urticaria
`Bullous or exfoliative skin lesions
`
`
`Reporting of suspected adverse reactions
`Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
`allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
`professionals are asked to report any suspected adverse reactions via the national reporting system
`listed in Appendix V.
`
`4.9 Overdose
`
`Information regarding overdose with vildagliptin is limited.
`
`Symptoms
`Information on the likely symptoms of overdose was taken from a rising dose tolerability study in
`healthy subjects given Galvus for 10 days. At 400 mg, there were three cases of muscle pain, and
`individual cases of mild and transient paraesthesia, fever, oedema and a transient increase in lipase
`levels. At 600 mg, one subject experienced oedema of the feet and hands, and increases in creatine
`phosphokinase (CPK), aspartate aminotransferase (AST), C-reactive protein (CRP) and myoglobin
`levels. Three other subjects experienced oedema of the feet, with paraesthesia in two cases. All
`symptoms and laboratory abnormalities resolved without treatment after discontinuation of the study
`medicinal product.
`
`Management
`In the event of an overdose, supportive management is recommended. Vildagliptin cannot be removed
`by haemodialysis. However, the major hydrolysis metabolite (LAY 151) can be removed by
`haemodialysis.
`
`
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`PHARMACOLOGICAL PROPERTIES
`
`5.
`
`5.1 Pharmacodynamic properties
`
`Pharmacotherapeutic group: Drugs used in diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC
`code: A10BH02
`
`Vildagliptin, a member of the islet enhancer class, is a potent and selective DPP-4 inhibitor.
`
`Mechanism of action
`The administration of vildagliptin results in a rapid and complete inhibition of DPP-4 activity,
`resulting in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1
`(glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).
`
`Pharmacodynamic effects
`By increasing the endogenous levels of these incretin hormones, vildagliptin enhances the sensitivity
`of beta cells to glucose, resulting in improved glucose-dependent insulin secretion. Treatment with
`vildagliptin 50-100 mg daily in patients with type 2 diabetes significantly improved markers of beta
`cell function including HOMA- (Homeostasis Model Assessment–), proinsulin to insulin ratio and
`measures of beta cell responsiveness from the frequently-sampled meal tolerance test. In non-diabetic
`(normal glycaemic) individuals, vildagliptin does not stimulate insulin secretion or reduce glucose
`levels.
`
`By increasing endogenous GLP-1 levels, vildagliptin also enhances the sensitivity of alpha cells to
`glucose, resulting in more glucose-appropriate glucagon secretion.
`
`The enhanced increase in the insulin/glucagon ratio during hyperglycaemia due to increased incretin
`hormone levels results in a decrease in fasting and postprandial hepatic glucose production, leading to
`reduced glycaemia.
`
`The known effect of increased GLP-1 levels delaying gastric emptying is not observed with
`vildagliptin treatment.
`
`Clinical efficacy and safety
`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.
`
`Overall, vildagliptin improved glycaemic control when given as monotherapy or when used in
`combination with metformin, a sulphonylurea, and a thiazolidinedione, as measured by clinically
`relevant reductions in HbA1c from baseline at study endpoint (see Table 8).
`
`In clinical trials, the magnitude of HbA1c reductions with vildagliptin was greater in patients with
`higher baseline HbA1c.
`
`In a 52-week double-blind controlled trial, vildagliptin (50 mg twice daily) reduced baseline HbA1c by
`-1% compared to -1.6% for metformin (titrated to 2 g/day) statistical non-inferiority was not achieved.
`Patients treated with vildagliptin reported significantly lower incidences of gastrointestinal adverse
`reactions versus those treated with metformin.
`
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`
`In a 24-week double-blind controlled trial, vildagliptin (50 mg twice daily) was compared to
`rosiglitazone (8 mg once daily). Mean reductions were -1.20% with vildagliptin and -1.48% 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 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 HbA1c was -0.5% for vildagliptin and -0.6% for
`gliclazide, from a mean baseline HBA1c 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 HbA1c 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 HbA1c were -0.4% with vildagliptin added to metformin
`and -0.5% with glimepiride added to metformin, from a mean baseline HbA1c 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 HbA1c was similar to baseline values in both treatment groups and the
`body weight changes and hypoglycaemia differences were maintained.
`
`In a 52-week trial, vildagliptin (50 mg twice daily) was compared to gliclazide (mean daily dose:
`229.5 mg) in patients inadequately controlled with metformin (metformin dose at baseline
`1928 mg/day). After 1 year, mean reductions in HbA1c were -0.81% with vildagliptin added to
`metformin (mean baseline HbA1c 8.4%) and -0.85% with gliclazide added to metformin (mean
`baseline HbA1c 8.5%); statistical non-inferiority was achieved (95% CI -0.11 – 0.20). Body weight
`change with vildagliptin was +0.1 kg compared to a weight gain of +1.4 kg with gliclazide.
`
`In a 24-week trial the efficacy of the fixed dose combination of vildagliptin and metformin (gradually
`titrated to a dose of 50 mg/500 mg twice daily or 50 mg/1000 mg twice daily) as initial therapy in
`drug-naïve patients was evaluated. Vildagliptin/metformin 50 mg/1000 mg twice daily reduced HbA1c
`by -1.82%, vildagliptin/metformin 50 mg/500 mg twice daily by -1.61%, metformin 1000 mg twice
`daily by -1.36% and vildagliptin 50 mg twice daily by -1.09% from a mean baseline HbA1c of 8.6%.
`The decrease in HbA1c observed in patients with a baseline ≥10.0% was greater.
`
` 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 HbA1c compared with placebo
`(difference of -0.53%) from a mean baseline of 7.9%. In patients with severe renal impairment,
`vildagliptin significantly decreased HbA1c compared with placebo (difference of -0.56%) from a mean
`baseline of 7.7%.
`
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`A 24-week randomised, double-blind, placebo-controlled trial was conducted in 318 patients to
`evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with metformin
`(≥1500 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 a mean baseline HbA1c of 8.8% was -0.76%.
`
` A
`
` 24-week randomised, 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 units), with concomitant use of metformin (N=276)
`or without concomitant metformin (N=173). Vildagliptin in combination with insulin significantly
`decreased HbA1c compared with placebo. In the overall population, the placebo-adjusted mean
`reduction from a mean baseline HbA1c 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. Patients receiving vildagliptin experienced no
`weight gain (+0.2 kg) while those receiving placebo experienced weight reduction (-0.7 kg).
`
`In another 24-week study in patients with more advanced type 2 diabetes not adequately controlled on
`insulin (short and longer acting, average insulin dose 80 IU/day), the mean reduction in HbA1c when
`vildagliptin (50 mg twice daily) was added to insulin was statistically significantly greater than with
`placebo plus insulin (0.5% vs. 0.2%). The incidence of hypoglycaemia was lower in the vildagliptin
`group than in the placebo group (22.9% vs. 29.6%).
`
` A
`
` 52-week multi-centre, randomised, double-blind trial was conducted in patients with type 2 diabetes
`and congestive heart failure (NYHA functional class I-III) to evaluate the effect of vildagliptin 50 mg
`twice daily (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 balanced overall. There were more cardiac events in
`vildagliptin treated patients with NYHA class III heart failure compared to placebo. However, there
`were imbalances in baseline cardiovascular risk favouring placebo and the number of events was low,
`precluding firm conclusions. Vildagliptin significantly decreased