Galvus Met: Galvus Met is not a substitute for insulin in insulin-requiring patients. It should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Vildagliptin: Hepatic Impairment: Vildagliptin is not recommended in patients with hepatic impairment, including patients with a pre-treatment ALT or AST >2.5 x ULN.
Liver Enzyme Monitoring: Rare cases of hepatic dysfunction (including hepatitis) have been reported with vildagliptin. 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 Galvus Met. Galvus Met is not recommended in patients with a pre-treatment ALT or AST >2.5 x ULN. LFTs should be monitored during Galvus Met treatment at 3-month intervals during the 1st year and periodically thereafter. Patients who develop increased transaminase levels should be monitored with a 2nd liver function evaluation to confirm the finding and be followed thereafter with frequent LFTs until the abnormality(ies) return to normal. Should an increase in AST or ALT of ≥3 x ULN persist, withdrawal of therapy with Galvus Met is recommended. Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue Galvus Met and contact their physician immediately. Following withdrawal of treatment with Galvus Met and LFT normalisation, Galvus Met should not be reinitiated.
Galvus Met is not recommended in patients with hepatic impairment.
Heart Failure: Vildagliptin is generally not recommended in patients with New York Heart Association (NYHA) class III unless the benefits outweigh the potential risks: 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 preexisting congestive heart failure versus placebo. Rates of reported cardiac adverse events were slightly higher in patients with NYHA functional class III treated with vildagliptin than with placebo, though a baseline imbalance in cardiovascular risk favoring the placebo arm and small numbers of patients in the NYHA class III sub-group preclude firm conclusions (see Pharmacology: Pharmacodynamics under Actions).
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.
Metformin HCl: Lactic Acidosis: Lactic acidosis is a very rare but serious metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by also assessing other associated risk factors eg, poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any conditions associated with hypoxia (see Contraindications and Interactions).
Diagnosis of Lactic Acidosis: Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels >5 mmol/L and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment with Galvus Met should be discontinued and the patient hospitalised immediately (see Overdosage).
Monitoring of Renal Function: Metformin HCl is known to be substantially excreted by the kidney, and the risk of metformin HCl accumulation and lactic acidosis increases with the degree of renal function impairment. Patients with serum creatinine levels above the ULN for their age should not receive Galvus Met. Since advancing age is associated with reduced renal function, Galvus Met should be carefully titrated in the elderly to establish the minimum dose for adequate glycemic effect, and renal function should be monitored regularly. Also, special caution should be exercised where renal function may become impaired eg, when initiating antihypertensive or diuretic therapy or when starting treatment with a nonsteroidal anti-inflammatory drug (NSAID). Renal function should be assessed and verified as normal before the initiation of Galvus Met, then at least once a year in patients with normal renal function and at least 2-4 times a year in patients with serum creatinine levels at the ULN. Additionally, patients in whom renal dysfunction is anticipated, should have their renal function assessed more frequently. Galvus Met should be discontinued if evidence of renal impairment is present.
Concomitant Medications that May Affect Renal Function or Metformin HCl Disposition: Concomitant medications that may affect renal function, result in significant hemodynamic change or interfere with the disposition of metformin HCl eg, cationic drugs that are eliminated by renal tubular secretion should be used with caution (see Interactions).
Administration of Intravascular Iodinated Contrast Materials: Galvus Met should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function and increase the risk of lactic acidosis. In patients undergoing such studies, Galvus Met should be temporarily discontinued at the time of or prior to the procedure, withheld for 48 hrs subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.
Hypoxic States: Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia. If such events occur in patients receiving Galvus Met therapy, the medication should be promptly discontinued.
Surgical Procedures: Use of Galvus Met 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.
Alcohol Intake: Alcohol is known to potentiate the effect of metformin HCl on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving Galvus Met.
Impaired Hepatic Function: Since impaired hepatic function has been associated with some cases of lactic acidosis, a risk associated with metformin HCl, Galvus Met should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 Levels: The metformin component of Galvus Met has been associated with a decrease in serum vitamin B12 levels without clinical manifestations, in approximately 7% of patients. Such decrease, is very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin HCl and/or vitamin B12 supplementation. Measurement of hematological parameters on at least an annual basis is advised for patients receiving Galvus Met and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (eg, those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at minimally 2- to 3-year intervals may be useful.
Change in Clinical Status of Patients With Previously Controlled Type 2 Diabetes: A patient with type 2 diabetes previously well-controlled on Galvus Met 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, Galvus Met must be stopped immediately and appropriate measures initiated.
Hypoglycaemia: Hypoglycaemia does not usually occur in patients receiving Galvus Met alone, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or ethanol use. Elderly, debilitated or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people taking β-adrenergic blocking drugs.
Loss of Control of Blood Glucose: When a patient stabilized on any diabetic regimen is exposed to stress eg, fever, trauma, infection, surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Galvus Met and temporarily administer insulin. Galvus Met may be reinstituted after the acute episode is resolved.
Effects on the Ability to Drive or Operate Machinery: 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.
Use in Pregnancy: Fertility studies have been performed with vildagliptin in rats at doses producing exposures equivalent to up to 200 times the human dose and have revealed no evidence of impaired fertility or early embryonic development due to vildagliptin. Embryofetal development (teratology) studies have been conducted in rats and rabbits with the combination of vildagliptin and metformin HCl in a 1:10 ratio and produced no evidence of teratogenicity in either species. There are, however, no adequate and well-controlled studies in pregnant women and therefore, Galvus Met should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Animal studies are not always predictive of human response.
Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased neonatal morbidity and mortality, most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible.
Use in Lactation: No studies have been conducted with the combined components of Galvus Met. As it is not known whether vildagliptin and/or metformin HCl is excreted in human milk, Galvus Met should not be administered to breastfeeding women.
Use in Children: Safety and effectiveness of Galvus Met in pediatric patients have not been established. Therefore, Galvus Met is not recommended for use in children <18 years.