Vildagliptin/ Metformin

Registered South African indications:

• Type 2 diabetes mellitus (T2DM):
  - As an adjunct to diet and exercise in patients who are already stabilised with the combination of vildagliptin and metformin hydrochloride at the same dosages, as separate tablets
  - As add-on to insulin as an adjunct to diet and exercise in patients on a stable dose of insulin plus vildagliptin and metformin hydrochloride
  - As an add-on to insulin at the same dosages as the separate tablets of vildagliptin and metformin hydrochloride
  - In combination with sulphonylurea (SU) (i.e. triple combination therapy) as an adjunct to diet and exercise in patients stabilised on vildagliptin, metformin hydrochloride and a sulphonylurea

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Severe renal impairment (GFR<30ml/min)
• Hepatic impairment, including patients with a pretreatment ALT or AST >2.5 x the upper limit of normal
• Congestive heart failure requiring pharmacological treatment
• Acute or chronic metabolic acidosis, including lactic acidosis or diabetic ketoacidosis, with or without coma. (Diabetic ketoacidosis should be treated with insulin)

South African recommendations

Caution recommended in the following patient groups

• Pregnancy
• Breastfeeding
• Mild to moderate renal impairment (GFR≥30ml/min)
• Elderly

Precautions related to the combination product

Patient requiring insulin

• This combination product is not a substitute for insulin in patients requiring insulin

Type 1 diabetes

• Vildagliptin/metformin should not be used in patients with type 1 diabetes

Treatment of diabetic ketoacidosis

• Vildagliptin/metformin should not be used for the treatment of diabetic ketoacidosis. (see Contraindications)

Alcohol intake

• Excessive consumption or acute intoxication increases the risk of lactic acidosis by potentiating the effect of metformin on lactate metabolism, particularly during fasting or malnutrition

Administration of intravascular iodinated contrast materials

• The medicine must be temporarily discontinued prior to, or at the time of radiologic studies involving intravascular iodinated contrast to avoid acute renal alteration and lactic acidosis

Precautions related to vildagliptin

Hepatic impairment

• Vildagliptin is not recommended in patients with hepatic impairment, including patients with pretreatment ALT or AST > 2.5 x the ULN. (see Contraindications)

Liver enzyme monitoring (see also Monitoring)

• Cases of hepatic dysfunction (including hepatitis) have been reported with vildagliptin
• 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 is recommended
• Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue vildagliptin/metformin and contact their physician immediately
• Following withdrawal of treatment and LFT normalisation, vildagliptin/metformin should not be reinitiated

Heart failure

• A clinical study 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
• Not recommended for those with NYHA functional class IV

Arthralgia

• Vildagliptin, as contained in this combination product, may cause arthralgia that can be severe

Severe cutaneous adverse reactions (SCARs)

• Therapy must be immediately discontinued if a patient develops reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis, which are regarded as a class effect of DPP-4 inhibitors

Rhabdomyolysis

• Requires close monitoring in patients with predisposing factors such as renal failure, hypovolemia, or concomitant use of statins and colchicine

Precautions related to metformin

Lactic acidosis

• Risk increases with acute worsening of renal function, cardiorespiratory illness, sepsis, dehydration (severe diarrhea/vomiting), or the use of medications that impair renal function (antihypertensives, diuretics, NSAIDs)
• In case of dehydration (e.g. due to severe diarrhoea or vomiting, fever or reduced fluid intake), the patient should stop taking metformin-containing products and seek immediate medical attention
• Metformin accumulation occurs with acute worsening of renal function and increases the risk of lactic acidosis
• Predisposing factors include excessive alcohol intake, hepatic impairment, poorly controlled diabetes, ketosis, prolonged fasting, and any conditions associated with hypoxia

Diagnosis of lactic acidosis

• Patients and/or caregivers should be informed of the risk of lactic acidosis. Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia, followed by coma
• Diagnostic laboratory findings are decreased blood pH (<7.35), increased plasma lactate levels >5mmol/L and an increased anion gap and lactate/pyruvate ratio
• If metabolic acidosis is suspected, treatment with metformin-containing products  should be discontinued, and the patient should be immediately hospitalised

Renal function

• Metformin-containing products are contraindicated in patients with GFR<30ml/min and should be temporarily discontinued in the presence of conditions that alter renal function (see Contraindications)
• Metformin hydrochloride is substantially excreted by the kidneys, and the risk of metformin hydrochloride accumulation and lactic acidosis increases with the degree of renal function impairment

Concomitant medications that may affect renal function or metformin hydrochloride disposition

• Concomitant medications that may affect renal function, result in significant haemodynamic change or interfere with the disposition of metformin hydrochloride, such as cationic medicines that are eliminated by renal tubular secretion, should be used with caution

Hypoxic states

• Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction and other conditions characterised by hypoxaemia have been associated with lactic acidosis and may also cause prerenal uraemia. If such events occur in patients receiving  therapy, the medication should be promptly discontinued

Surgical procedures

• Use should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal

Hepatic function

• Since impaired hepatic function has been associated with some cases of lactic acidosis, a risk associated with metformin hydrochloride, metformin-containing products  should generally be avoided in patients with clinical or laboratory evidence of hepatic disease

Vitamin B₁₂ levels

• Metformin may decrease serum vitamin B₁₂ levels; patients with inadequate intake or absorption are particularly predisposed and require regular monitoring

Change in clinical status of patients with previously controlled type 2 diabetes

• A patient with type 2 diabetes previously well-controlled on vildagliptin/metformin who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should promptly be evaluated for ketoacidosis and/or lactic acidosis
• If acidosis of either form occurs, vildagliptin/metformin must be stopped immediately and appropriate measures initiated

Hypoglycaemia

• Susceptibility increases with deficient caloric intake, strenuous uncompensated exercise, ethanol use, or in patients who are elderly, debilitated, malnourished, or have adrenal/pituitary insufficiency
• Hypoglycaemia may occur when vildagliptin/metformin is used as add-on therapy to other anti-diabetic medicines

Loss of control of blood glucose

• When a patient stabilised on any diabetic regimen is exposed to stress such as fever, trauma, infection, surgery, etc., a temporary loss of glycaemic control may occur
• At such times, it may be necessary to withhold vildagliptin/metformin and temporarily administer insulin. Vildagliptin/metformin may be reinstituted after the acute episode is resolved

Effect on ability to drive and use machines

• May cause dizziness. Patients who experience dizziness should avoid driving vehicles or using machines

Forms avail. in SA and covered in this monograph: fct, tab

South African registered indications and dosages

Type 2 diabetes mellitus (T2DM):
- As an adjunct to diet and exercise in patients who are already stabilised with the combination of vildagliptin and metformin hydrochloride at the same dosages, as separate tablets
- As add-on to insulin as an adjunct to diet and exercise in patients on a stable dose of insulin plus vildagliptin and metformin hydrochloride
- As an add-on to insulin at the same dosages as the separate tablets of vildagliptin and metformin hydrochloride
- In combination with sulphonylurea (SU) (i.e. triple combination therapy) as an adjunct to diet and exercise in patients stabilised on vildagliptin, metformin hydrochloride and a sulphonylurea

Metformin/ Vildagliptin
850/50 (mg)
1000/50 (mg)

• Oral (fct, tab): Initial combination dose should be based on the patient's current regimen of vildagliptin and/or metformin hydrochloride; Max: 100mg vildagliptin/24hrs

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Vildagliptin/ metformin can be used to replace the vildagliptin and metformin hydrochloride at the same dosages as the separate tablets

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Vildagliptin/ metformin should be given with meals to reduce the gastrointestinal side effects associated with metformin hydrochloride

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Use in combination with sulphonylurea or with insulin: The dose of vildagliptin/ metformin should provide vildagliptin dosed as 50mg twice daily (100mg total daily dose) and a dose of metformin similar to the dose already being taken

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Caution; not recommended
• Safety in pregnancy has not been established

Breastfeeding

South African recommendations

• Caution; not recommended
• Safety in lactation has not been established
• Vildagliptin/metformin should not be administered to breastfeeding women

Fertility

South African recommendations

• No information available

South African recommendations

• GFR≥30ml/min: Caution; dose adjustment recommended
  The max. daily dose of metformin should preferably be divided into 2-3 daily doses
  Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of metformin-containing products in patients with GFR<60ml/min
• GFR<30ml/min: Contraindicated

The following dosing recommendations apply to metformin and vildagliptin, used separately or in combination, in patients with renal impairment. If no adequate strength of vildagliptin/metformin is available, individual components should be used instead of the fixed dose combination

GFR ml/min	Metformin	Vildagliptin
60-89	Maximum daily dose is 3000 mg*. Dose reduction may be considered if renal function declines	Maximal daily dose is 100mg
45-59	Starting dose should not be more than 1000mg with a maximum daily dose of 2000mg*	Maximal daily dose is 50mg
30-44	Starting dose should not be more than 500mg with a maximum daily dose of 1000mg
<30	Metformin is contraindicated

*If metformin doses higher than those achievable with vildagliptin/metformin alone are considered necessary

South African recommendations

• Contraindicated
  Vildagliptin/metformin is contraindicated in patients with hepatic impairment, including patients with a pretreatment ALT or AST >2.5 x the upper limit of normal

South African recommendations

• Caution; dose adjustment recommended
  As metformin is excreted via the kidneys, and elderly patients tend to exhibit decreased renal function, elderly patients taking metformin-containing products should have their renal function monitored regularly
  The dosage of vildagliptin/metformin for elderly patients should be adjusted based on renal function (see Renal Impairment)

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Vildagliptin
Central Nervous System Disorders

• Headache
• Dizziness

Cardiovascular Disorders

• Peripheral oedema

Gastrointestinal Disorders

• Constipation
• Pancreatitis

Hepatobiliary Disorders

• Hepatitis
• Abnormal hepatic function tests

Endocrine and Metabolic Disorders

• Hypoglycaemia

Musculoskeletal Disorders

• Athralgia
• Myalgia

Skin and Subcutaneous Tissue Disorders

• Urticaria
• Bullous skin lesions
• Exfoliative skin lesions

Metformin
Central Nervous System Disorders

• Taste disturbances

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Abdominal pain
• Loss of appetite

Hepatobiliary Disorders

• Abnormal hepatic function tests
• Hepatitis 

Genitourinary Disorders 

• Ketoacidocis
• Ketonuria

Endocrine and Metabolic Disorders

• Lactic acidosis 
• Decreased vitamin B12 absorption 

Skin and Subcutaneous Tissue Disorders 

• Erythema
• Pruritus
• Urticaria

Immune, Blood and Lymphatic System Disorders 

• Megaloblastic anaemia

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Vildagliptin

• Angiotensin converting enzyme inhibitors
• Thiazide diuretics
• Corticosteroids
• Thyroid treatment
• Sympathomimetics 

Metformin

• Alcohol 
• Iodinated contrast agents 
• Non-steroidal anti-inflammatory drugs
• Angiotensin converting enzyme inhibitors 
• Angiotensin II receptor antagonists 
• Diuretics 
• Glucocorticoids 
• Sympathomimetics 
• Organic cation transporters inhibitors 
• Organic cation transporters inducers 
• Warfarin 
• Sulphonylurea 
• Insulin
• Oral antidiabetic agents

• Hepatic function
  - Liver function tests (LFTs) should be performed prior to the initiation of treatment
  - LFTs should be monitored during treatment at 3 month intervals during the first year and periodically thereafter
• Renal function
  - GFR should be assessed before initiation of treatment and at least annually thereafter
  - In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months

Specific cases may require

• Serum B12 
• Cardiac function 

Vildagliptin
Vildagliptin acts by inhibiting dipeptidyl peptidase 4 activity which results in increased fasting and postprandial endogenous levels of the incretin hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide. Increased levels of these incretin hormones sensitize beta cells to glucose, resulting in improved glucose-dependent insulin secretion from the pancreas. Increased levels of incretin hormones also suppress glucagon secretion from pancreatic alpha cells when blood glucose is normal or elevated 

Metformin
Metformin is a biguanide which decreases basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia. Metformin reduces hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis and it increases insulin sensitivity, improving peripheral glucose uptake and utilisation and it delays intestinal glucose absorption. Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase and increases the transport capacity of all types of membrane glucose transporters known to date.

COMBINATION PREPARATIONS

Metformin/ Vildagliptin

Tablet 850mg/50mg

• Jalramet (Norvartis)
• Galvus Met (Novartis) originator

Tablet 1000mg/50mg

• Jalramet (Novartis)
• Galvus Met (Novartis) originator