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Drug Details

GALVUS Tablets

• Drug Class Description
  Dipeptidyl peptidase 4 (DPP-4) inhibitors
• Generic Name
  Vildagliptin
• Presentation
  Tablet White to light yellowish, round (8mm diameter), flat-faced, bevelled-edge tablet. One side is debossed with “NVR”, and the other side with “FB”.
• Description
  Each tablet contains 50mg of vildagliptin. Excipient: Each tablet contains 47.82mg anhydrous lactose
• Indications
  

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

• Adult Dosage
  

  Adults

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

  When used in dual combination with a sulphonylurea, the recommended dose of vildagliptin is 50mg once daily administered in the morning. In this patient population, vildagliptin 100mg daily was no more effective than vildagliptin 50mg once daily.

  Doses higher than 100mg are not recommended.

  The safety and efficacy of vildagliptin as triple oral therapy in combination with metformin and a thiazolidinedione or with metformin and a sulphonylurea has not been established.

  Galvus can be administered with or without a meal.

  Additional information on special populations

  Renal impairment

  No dose adjustment is required in patients with mild renal impairment (creatinine clearance 50ml/min). The use of Galvus is not recommended in patients with moderate or severe renal impairment or in haemodialysis patients with end-stage renal disease (ESRD).

  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).

  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.

  Paediatric population (< 18 years)

  Galvus is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.

• Child Dosage
  Paediatric population ( < 18 years) - Galvus is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.
• Elderly Dosage
  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.
• Contra Indications
  

  Hypersensitivity to the active substance or to any of the excipients.

• Special Precautions
  

  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 moderate to severe renal impairment or in patients with ESRD on haemodialysis. Therefore, the use of Galvus is not recommended in these patients.

  Hepatic impairment

  Galvus should not be used in patients with hepatic impairment, including patients with pre-treatment ALT or AST> 3x 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 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

  Experience with vildagliptin therapy in patients with congestive heart failure of New York Heart Association (NYHA) functional class III 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 IIIIV 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. 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.

  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.

• Interactions
  

  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.

• Adverse Drug Reactions
  

  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 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 50mg once daily, vildagliptin 50mg 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, <1/10), uncommon (1/1,000, <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 (+0.2kg and 1.0kg 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)

  Nervous system disorders
  Common	Tremor
  Common	Headache
  Common	Dizziness
  Uncommon	Fatigue
  Gastrointestinal disorders
  Common	Nausea
  Metabolism and nutrition disorders
  Common	Hypoglycaemia

  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 (0.1kg and 0.4kg 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)

  Infections and infestations
  	Very rare	Nasopharyngitis
  Nervous system disorders
  	Common	Tremor
  	Common	Headache
  	Common Common	Dizziness Asthenia
  Gastrointestinal disorders
  	Uncommon	Constipation
  Metabolism and nutrition disorders
  	Common	Hypoglycaemia

  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 2.7kg, respectively.

  The incidence of peripheral oedema when vildagliptin 100mg daily was added to a maximum dose of background pioglitazone (45mg 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)

  Nervous system disorder
  	Uncommon	Headache
  	Uncommon	Asthenia
  Metabolism and nutrition disorders
  	Common Uncommon	Weight increase Hypoglycaemia
  Vascular disorders
  	Common	Oedema peripheral

  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 (0.3kg and 1.3kg for vildagliptin and placebo, respectively).

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

  Nervous system disorder
  	Common	Dizziness
  	Uncommon	Headache
  Gastrointestinal disorders
  	Uncommon	Constipation
  Musculoskeletal and connective tissue disorders
  	Uncommon	Arthralgia
  Metabolism and nutrition disorders
  	Uncommon	Hypoglycaemia
  Infections and infestations
  	Very rare	Upper respiratory tract infection
  	Very rare	Nasopharyngitis
  Vascular disorders
  	Uncommon	Oedema peripheral