Fixed_Dose-Alogliptin / Metformin

Alogliptin /Metformin 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.

Alogliptin /Metformin can also be used to replace separate tablets of alogliptin and metforminin individuals already being treated with this combination.

For the latest PBS indications for Alogliptin /Metformin please see
https://www.pbs.gov.au/medicine/item/10032B-10033C-10035E

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.

• Alogliptin /Metformin 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 alogliptin /metformin should be individualised 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.
• Alogliptin /Metformin is not indicated for initial combination therapy.
• Individuals inadequately managed on metformin alone: For individuals inadequately managed on metformin alone, the recommended dose of alogliptin /metformin should provide alogliptin dosed at 12.5 mg twice daily (25 mg total daily dose) and metformin 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 alogliptin /metformin administered concomitantly; alogliptin should be dosed at 12.5 mg twice daily (25 mg total daily dose) and metformin 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 alogliptin /metformin 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 alogliptin /metformin is necessary. Due to its metformin component, alogliptin /metformin should not be used in individuals with moderate or severe renal impairment. Appropriate assessment of renal function is recommended prior to initiation of alogliptin /metformin and at regular intervals thereafter.
• Hepatic impairment: Due to its metformin component, alogliptin /metformin should not be used in those with hepatic impairment.

• No dose adjustment is necessary based on age. However, dosing of alogliptin /metformin 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 ketoacidosis, coma or pre-coma. Ketoacidosis should be treated with insulin.
• Known hypersensitivity to alogliptin, metformin or any of the excipients.
• Alogliptin /metformin 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 – Alogliptin /Metformin 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 alogliptin /metformin 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).
  – 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 alogliptin /metformin.
  – Surgery: As alogliptin /metformin 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 alogliptin /metformin 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.
  
• Alogliptin
  – Hypersensitivity Reactions: Post marketing events of serious hypersensitivity reactions in people 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, alogliptin /metformin 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, individuals should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, alogliptin /metformin 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 those 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 individuals 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.