Name of Medicine
Linagliptin and metformin hydrochloride
Presentation
- TRAJENTAMET are film-coated tablets for oral administration:
-TRAJENTAMET 2.5 mg/500 mg contains 2.5 mg linagliptin and 500 mg metformin hydrochloride
-TRAJENTAMET 2.5 mg/850 mg contains 2.5 mg linagliptin and 850 mg metformin hydrochloride
-TRAJENTAMET 2.5 mg/1000 mg contains 2.5 mg linagliptin and 1000 mg metformin hydrochloride.
Key Practice Points
Therapeutic Indications:
- TRAJENTAMET is indicated as an adjunct to heathy eating and physical activity to improve glycaemic management in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate, in individuals inadequately managed on metformin alone, or those already being treated and managed with the free combination of linagliptin and metformin.
- TRAJENTAMET is indicated in combination with a sulfonylurea (i.e., triple combination therapy) as an adjunct to heathy eating and physical activity to improve glycaemic management on their maximal tolerated dose of metformin and a sulfonylurea.
- TRAJENTAMET is indicated in combination with an SGLT2 inhibitor (i.e., triple combination therapy)
-as an adjunct to healthy eating and physical activity in individuals inadequately managed on their maximum tolerated dose of metformin and an SGLT2 inhibitor.
- TRAJENTAMET is indicated as add-on to insulin (i.e., triple combination therapy) as an adjunct to
-healthy eating and physical activity in individuals inadequately managed when insulin and metformin alone does not provide adequate glycaemic management.
For the latest PBS indications for Trajenamet please see
https://www.pbs.gov.au/pbs/search?analyse=false&term=trajentamet&search-type=medicines
Dose:
Life threatening lactic acidosis can occur due to accumulation of metformin. The main risk factor is renal impairment, other risk factors include old age associated with reduced renal function and high doses of metformin above 2g per day.
– TRAJENTAMET is contraindicated in individuals with severe renal failure (creatinine clearance < 30 mL/min or eGFR < 30 mL/min/1.73m2) due to the metformin component.
– Renal function should be assessed before initiation of treatment with metformin containing products and at least annually thereafter.
– In individuals at an 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.
- Adults with normal renal function (GFR ≥ 90mL/min):
- -The recommended dose is TRAJENTAMET 2.5 mg/500 mg, 2.5 mg/850 mg or 2.5 mg/1000 mg twice daily.
- -The dosage should be individualised based on the person’s current regimen, effectiveness, and tolerability. Maximum recommended daily dose of TRAJENTAMET is 5 mg of linagliptin and 2000 mg of metformin.
- -TRAJENTAMET should be given with meals to reduce the gastrointestinal undesirable effects associated with metformin.
- For individuals currently not treated with metformin:-For individuals currently not treated with metformin, the recommended starting dose is TRAJENTAMET 2.5 mg linagliptin/500 mg metformin hydrochloride twice daily.
- For individuals inadequately managed on maximal tolerated dose of metformin monotherapy:-For individuals not adequately managed on metformin alone, the usual starting dose of TRAJENTAMET should provide linagliptin dosed as 2.5 mg twice daily (5 mg total daily dose) plus the dose of metformin already being taken.
- For individuals switching from co-administration of linagliptin and metformin:-For individuals switching from co-administration of linagliptin and metformin to the fixed dose combination, TRAJENTAMET should be initiated at the dose of linagliptin, and metformin already being taken.
- For individuals inadequately managed on dual combination therapy with the maximal tolerated dose of metformin and a sulfonylurea:-The dose of TRAJENTAMET should provide linagliptin dosed as 2.5 mg twice daily (5 mg total daily dose) and a dose of metformin like the dose already being taken. When TRAJENTAMET is used in combination with a sulfonylurea, a lower dose of the sulfonylurea may be required to reduce the risk of hypoglycaemia.
- For individuals inadequately managed on dual combination therapy with insulin and the maximal tolerated dose of metformin:-The dose of TRAJENTAMET provide linagliptin dosed as 2.5 mg twice daily (5 mg total daily dose) and a dose of metformin like the dose already being taken. When TRAJENTAMET is used in combination with insulin, a lower dose of insulin may be required to reduce the risk of hypoglycaemia.
- Renal impairment:
– TRAJENTAMET is contraindicated in individuals with severe renal failure (creatinine clearance < 30 mL/min or eGFR < 30 mL/min/1.73m2) due to the metformin component.
– Renal function should be assessed before initiation of treatment with metformin containing products and at least annually thereafter.
– In individuals at an 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.
- Hepatic impairment:
– TRAJENTAMET is contraindicated in those with hepatic impairment due to the metformin component.
Elderly:
As metformin is excreted via the kidney, and the elderly have a tendency for decreased renal function, elderly individuals taking TRAJENTAMET should have their renal function monitored regularly.
Contraindications:
- Hypersensitivity to active ingredients linagliptin and/or metformin hydrochloride or to any of the excipients.
- Any type of metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis)
- Diabetic pre-coma
- Severe renal failure (creatinine clearance < 30 mL/min or eGFR < 30 mL/min/1.73m2), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicaemia.
- Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock, intravascular administration of iodinated contrast agents.
- Acute or chronic disease which may cause tissue hypoxia such as: cardiac or respiratory failure, recent myocardial infarction, shock, pulmonary embolism, acute significant blood loss, sepsis, gangrene, pancreatitis.
- During or immediately following surgery where insulin is essential, elective major surgery.
- Hepatic impairment, acute alcohol intoxication, alcoholism (due to the metformin component)
- Lactation
- TRAJENTAMET must be temporarily discontinued in those undergoing radiologic studies involving intravascular administration of iodinated contrast materials because use of such products may result in acute alteration of renal function.
Precautions:
General – TRAJETAMET should not be used in individuals with type 1 diabetes
mellitus.
- Metformin
– Lactic acidosis: Lactic acidosis is a rare, but serious metabolic complication that can occur due to metformin accumulation during treatment with metformin. When it occurs, it is fatal in approximately 50% of cases. Lactic acidosis is a medical emergency and must be treated in hospital immediately. The risk of lactic acidosis increases with the degree of renal dysfunction. Reported cases of lactic acidosis in individuals on metformin have occurred primarily in those with diabetes with significant renal insufficiency, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Special caution should be taken in the elderly due to the decrease of renal function with age. Note: Diabetes MedsCheck with referral to healthcare team for education on lactic acidosis.
– Surgery: Metformin must be discontinued at the time of surgery under general, spinal or epidural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been re-evaluated and found to be stable.
– Monitoring of renal function: Renal function should be confirmed before initiation of TRAJETAMET therapy, and then at least once a year in those with normal renal function and at least two to four times a year if serum creatinine levels are at or above the upper limit of normal and in the elderly . Decreased renal function in the elderly is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive or diuretic therapy or when starting treatment with a nonsteroidal anti-inflammatory drug (NSAID). Note: Diabetes MedsCheck with referral for annual cycle of care for renal check.
– Alcohol Intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Individuals, therefore, should be warned against excessive alcohol intake while receiving TRAJENTAMET.
Adverse Effects:
- Metformin
– Gastrointestinal disorders: Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain, and loss of appetite are very common (>10%): these occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent these gastrointestinal symptoms, it is recommended that this medicinal product be taken in 2 or 3 daily doses. A slow increase of the dose may also improve gastrointestinal tolerability.
– Metabolism and nutrition disorders: Lactic acidosis is a very rare (<0.01%) but serious metabolic complication that can occur due to metformin accumulation during treatment with metformin. The onset of lactic acidosis is often subtle and accompanied only by non-specific symptoms such as malaise, myalgia, respiratory distress, increasing somnolence and non-specific abdominal distress. There may be associated hypothermia, hypotension and resistant bradyarrhythmias with more marked acidosis. Note: Diabetes MedsCheck with referral to healthcare team if suspected.
– Hepatobiliary disorders: Very rare: liver function test abnormalities or hepatitis requiring treatment discontinuation.
– Skin and subcutaneous tissue disorders: Skin reactions such as erythema, pruritus and urticaria have been reported but the incidence is very rare (<0.01%).
– Nervous system disorders
– Taste disturbance (3 %) is common.
– Vitamin B12 Levels: In controlled, 29-week clinical trials of immediate release metformin, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12- intrinsic factor complex is, however, very rarely associated with anaemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation. Measurement of haematologic parameters on an annual basis is advised in those on TRAJENTAMET and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels). See interventions for further information. - Linagliptin
– Combination with glucagon like peptide (GLP-1) analogues. Linagliptin has not been studied in combination with glucagon like peptide 1 (GLP-1) analogues.
– Pancreatitis: Acute pancreatitis has been observed in individuals taking linagliptin. If pancreatitis is suspected, TRAJENTAMET should be discontinued. Note: Diabetes MedsCheck with counselling on sided effect profile and referral to healthcare team if suspected.
– Bullous pemphigoid: Bullous pemphigoid has been observed in patients taking linagliptin. If bullous pemphigoid is suspected, TRAJENTAMET should be discontinued. Note: Diabetes MedsCheck with counselling on sided effect profile and referral to healthcare team if suspected.
Arthralgia: There have been post marketing reports of joint pain, which may be severe, in patients taking DPP4 inhibitors. Onset of symptoms following initiation of treatment may be rapid or may occur after longer periods. Discontinuation of therapy should be considered in individuals who present with or experience an exacerbation of joint symptoms during treatment with linagliptin. Note: Diabetes MedsCheck with counselling on sided effect profile and referral to healthcare team if suspected.
Pharmacokinetic Properties Summary
- Bioequivalence studies in healthy subjects demonstrated that the TRAJENTAMET (linagliptin/metformin hydrochloride) combination tablets are bioequivalent to co-administration of linagliptin and metformin hydrochloride as individual tablets following a single dose.
- Administration of TRAJENTAMET 2.5 mg/1000 mg with food resulted in no change in overall exposure of linagliptin. With metformin there was no change in AUC, however mean peak serum concentration of metformin was decreased by 18% when administered with food. A delayed time to peak serum concentrations by 2 hours was observed for metformin under fed conditions. These changes are not likely to be clinically significant.
Linagliptin
-The pharmacokinetics of linagliptin has been extensively characterized in healthy subjects and individuals with type 2 diabetes. After oral administration of a 5 mg dose to healthy volunteers, linagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1.5 hours post dose.
-Plasma concentrations of linagliptin decline in a triphasic manner with a long terminal half-life (terminal half-life for linagliptin more than 100 hours), that is mostly related to the saturable, tight binding of linagliptin to DPP-4 and does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of 5 mg linagliptin, is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of 5 mg linagliptin are reached by the third dose.
-Plasma AUC of linagliptin increased approximately 33% following 5 mg doses at steady state compared to the first dose.
-Plasma concentrations of linagliptin decline in a triphasic manner with a long terminal half-life (terminal half-life for linagliptin more than 100 hours), that is mostly related to the saturable, tight binding of linagliptin to DPP-4 and does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of 5 mg linagliptin, is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of 5 mg linagliptin are reached by the third dose.
-Plasma AUC of linagliptin increased approximately 33% following 5 mg doses at steady state compared to the first dose.
Absorption:
- The absolute bioavailability of linagliptin is approximately 30%. Because co-administration of a high fat meal with linagliptin had no clinically relevant effect on the pharmacokinetics, linagliptin may be administered with or without food.
Distribution:
- As a result of tissue binding, the mean apparent volume of distribution at steady state following a single 5 mg intravenous dose of linagliptin to healthy subjects is approximately 1110 litres, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at 1 nmol/L to 75-89% at ≥ 30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At the peak plasma concentration in humans at 5 mg/day, approximately 10% of linagliptin is unbound.
Metabolism:
Following a [14C] linagliptin oral 10 mg dose, approximately 5% of the
radioactivity was excreted in urine. Metabolism plays a subordinate role in the
elimination of linagliptin.
Excretion:
Following administration of an oral [14C]-linagliptin dose to healthy
subjects, approximately 85% of the administered radioactivity was eliminated in
faeces (80%) or urine (5%) within 4 days of dosing.
Metformin hydrochloride:
- Absorption: After an oral dose of metformin, Tmax is reached in 2.5 hours. Absolute bioavailability of a 500 mg or 850 mg metformin hydrochloride tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.
After oral administration, metformin hydrochloride absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin hydrochloride absorption is non-linear.
At the recommended metformin hydrochloride doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 microgram/mL. In controlled clinical trials, maximum metformin hydrochloride plasma levels (Cmax) did not exceed 5 microgram/mL, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin hydrochloride. Following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35-minute prolongation of the time to peak plasma concentration were observed. The clinical relevance of these decreases is unknown. - Distribution: Plasma protein binding is negligible. Metformin hydrochloride partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranged between 63-276 L.
- Metabolism: Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism.
- Excretion: Renal clearance of metformin hydrochloride is > 400 mL/min, indicating that metformin hydrochloride is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.
When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin hydrochloride in plasma.
For further information on TRAJENTAMET please see
https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2013-PI-01809-1
Distribution:
- As a result of tissue binding, the mean apparent volume of distribution at steady state following a single 5 mg intravenous dose of linagliptin to healthy subjects is approximately 1110 litres, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at 1 nmol/L to 75-89% at ≥ 30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At the peak plasma concentration in humans at 5 mg/day, approximately 10% of linagliptin is unbound.