Alogliptin (as benzoate), a dipeptidyl peptidase 4 (DPP-4) inhibitor, and metformin Hydrochloride.
- NESINA MET is available as film-coated tablets for oral administration containing alogliptin benzoate equivalent to 12.5 mg alogliptin free base and:
-500 mg metformin hydrochloride (12.5 mg/500 mg) or
-850 mg metformin hydrochloride (12.5 mg/850 mg) or
-1000 mg metformin hydrochloride (12.5 mg/1000 mg)
NESINA MET is indicated to improve glycaemic management in adult (≥ 18 years old) with type 2 diabetes mellitus when healthy eating and physical activity do not provide adequate glycaemic management and treatment with both alogliptin and metformin is appropriate,
-when treatment with metformin alone does not provide adequate management; or
-in combination with a thiazolidinedione or with insulin when dual therapy does not provide adequate management.
NESINA MET can also be used to replace separate tablets of alogliptin and metformin in individuals already being treated with this combination.
For the latest PBS indications for NesinaMet please see
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.
- NESINA MET should be taken orally twice daily with food with gradual dose escalation to reduce the gastrointestinal (GI) side effects due to metformin. The tablets should be swallowed whole with water. If a dose is missed, it should be taken as soon as the person remembers. A double dose should not be taken at the same time.
- Adults (≥ 18 years old): The recommended starting dose of NESINA MET should be individualized based on the person’s current regimen. Dosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25 mg alogliptin and 2000 mg metformin hydrochloride.
- NESINA MET is not indicated for initial combination therapy.
- Individuals inadequately managed on metformin alone: For individuals inadequately managed on metformin alone, the recommended dose of NESINA MET should provide alogliptin dosed at 12.5 mg twice daily (25 mg total daily dose) and metformin hydrochloride at a similar dose (either 500 mg, 850 mg or 1000 mg twice daily) to that already being taken.
- Individuals inadequately managed on dual therapy with metformin and a thiazolidinedione: For individuals inadequately managed on dual therapy with metformin and a thiazolidinedione, the dose of the thiazolidinedione should be maintained, and NESINA MET administered concomitantly; alogliptin should be dosed at 12.5 mg twice daily (25 mg total daily dose) and metformin hydrochloride at a similar dose (either 500 mg, 850 mg or 1000 mg twice daily) to that already being taken.
- Individuals inadequately managed on dual combination therapy with insulin and metformin: For individuals inadequately managed on dual combination therapy with insulin and metformin, the dose of NESINA MET should provide alogliptin dosed at 12.5 mg twice daily (25 mg total daily dose) and a dose of metformin like the dose already being taken. A lower dose of insulin may be considered to reduce the risk of hypoglycaemia.
- Individuals switching from separate tablets of alogliptin and metformin: For individuals switching from separate tablets of alogliptin and metformin, both alogliptin and metformin should be dosed at the total daily dose already being taken; the individual dose of alogliptin should be halved as it will be taken twice daily whilst the dosing of metformin (either 500 mg, 850 mg or 1000 mg twice daily) should remain unchanged.
- Renal impairment: For those with mild renal impairment, no dose adjustment of NESINA MET is necessary. Due to its metformin component, NESINA MET should not be used in patients with moderate or severe renal impairment. Appropriate assessment of renal function is recommended prior to initiation of NESINA MET and at regular intervals thereafter.
- Hepatic impairment: Due to its metformin component, NESINA MET should not be used in those with hepatic impairment.
- No dose adjustment is necessary based on age. However, dosing of NESINA MET should be conservative in individuals with advanced age due to the potential for decreased renal and cardiac function in this population.
- Renal disease or dysfunction (e.g., as suggested by serum creatinine levels ≥ 135 µmol/L for men, ≥ 110 µmol/L for women or creatinine clearance < 60 mL/min) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicaemia.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, diabetic coma or
- pre-coma. Diabetic ketoacidosis should be treated with insulin.
- Known hypersensitivity to alogliptin benzoate, metformin hydrochloride or any of the excipients.
- NESINA MET should be temporarily discontinued in individuals undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.
- General - NESINA MET 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.
-Monitoring of renal function: Renal function should be confirmed before initiation of NESINA MET 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 elderly patients. 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).
-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 NESINA MET.
-Surgery: As NESINA MET contains metformin, treatment should be discontinued 48 hours before elective surgery with general, spinal, or epidural anaesthesia. Treatment should not usually be resumed earlier than 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.
- 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 for education on lactic acidosis.
-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 NESINA MET 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.
-Hypersensitivity Reactions: Post marketing events of serious hypersensitivity reactions in patients treated with alogliptin such as angioedema and severe cutaneous adverse reactions including Stevens-Johnson syndrome have been reported and have been associated with other DPP-4 inhibitors. If a serious hypersensitivity reaction is suspected, NESINA MET should be discontinued.
-Acute Pancreatitis: Post marketing events of acute pancreatitis have been reported for alogliptin and have been associated with other DPP-4 inhibitors. After initiation of alogliptin, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, NESINA MET should be promptly discontinued, and appropriate management should be initiated.
Note: Diabetes MedsCheck with counselling on side 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 DPP-4 inhibitors. Onset of symptoms following initiation of treatment may be rapid or may occur after longer periods. Discontinuation of therapy should be considered in patients who present with or experience an exacerbation of joint symptoms during treatment with alogliptin.
Note: Diabetes MedsCheck with counselling on side effect profile and referral to healthcare team if suspected.
- The clinical studies conducted to support the efficacy of NESINA MET involved the coadministration of alogliptin and metformin as separate tablets. There have been no clinical efficacy studies conducted with NESINA MET tablets; however, the results of bioequivalence studies have demonstrated that NESINA MET film-coated tablets are bioequivalent to the corresponding doses of alogliptin and metformin co-administered as separate tablets.
- In bioequivalence studies of NESINA MET, the area under the curve (AUC) and maximum concentration (Cmax) of both the alogliptin and the metformin component following a single dose of the combination tablet were bioequivalent to the alogliptin 12.5 mg concomitantly administered with metformin hydrochloride 500 or 1000 mg tablets under fasted conditions in healthy subjects.
- Coadministration of 100 mg alogliptin once daily and 1000 mg metformin hydrochloride twice daily for 6 days in healthy subjects had no clinically relevant effects on the pharmacokinetics of alogliptin or metformin.
- Administration of NESINA MET with food resulted in no change in total exposure (AUC) to alogliptin or metformin. However, mean peak plasma concentrations of alogliptin and metformin were decreased by 13% and 28% when NESINA MET was administered with food, respectively. There was no change in the time to peak plasma concentration (Tmax) for alogliptin, but there was a delayed Tmax for metformin of 1.5 hours. These changes are not likely to be clinically significant.
- NESINA MET should be taken twice daily because of the pharmacokinetics of its metformin component. It should also be taken with meals to reduce the gastrointestinal undesirable effects associated with metformin.
- The absolute bioavailability of alogliptin is approximately 100%.
- Administration with a high-fat meal resulted in no change in total and peak exposure to alogliptin. Alogliptin may, therefore, be administered with or without food.
- After administration of single, oral doses of up to 800 mg in healthy subjects, alogliptin was rapidly absorbed with peak plasma concentrations occurring 1 to 2 hours (median Tmax) after dosing.
- No clinically relevant accumulation after multiple dosing was observed in either healthy subjects or in people type 2 with diabetes mellitus.
- Total and peak exposure to alogliptin increased proportionally across single doses of up to 100 mg alogliptin. The inter-subject coefficient of variation for alogliptin AUC was small (17%).
- The absolute bioavailability of a 500 mg metformin hydrochloride tablet given under fasting conditions is approximate 50 to 60%. Studies using single oral doses of metformin hydrochloride tablets 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination.
- Food decreases the extent of and slightly delays the absorption of metformin hydrochloride, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve, and a 35-minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin hydrochloride with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
- The absolute bioavailability of a 500 mg metformin hydrochloride tablet given under fasting conditions is approximate 50 to 60%. Studies using single oral doses of metformin hydrochloride tablets 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination.
- Food decreases the extent of and slightly delays the absorption of metformin hydrochloride, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve, and a 35-minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin hydrochloride with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
- Alogliptin: Alogliptin does not undergo extensive metabolism and 60-71% of the dose is excreted as unchanged drug in the urine. Two minor metabolites were detected following administration of an oral dose of [14C] alogliptin.
- Metformin: Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.
- Alogliptin: The recommended total daily dose of 25 mg alogliptin was eliminated with a mean terminal half-life (T1/2) of approximately 21 hours.
Following administration of an oral dose of [14C] alogliptin, 76% of total radioactivity was eliminated in the urine and involved some active renal tubular secretion, and 13% was recovered in the faeces. - Metformin: Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
For further information on Nesina Met please see
https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2013-PI-02391-1
