Clinic Diabetes

Fixed_Dose-Kombiglyze XR

Saxagliptin (as hydrochloride)/ metformin hydrochloride

  • KOMBIGLYZE XR 5/500 tablets containing 5 mg saxagliptin (as hydrochloride) immediate release and 500 mg metformin hydrochloride modified release.
  • KOMBIGLYZE XR 5/1000 tablets containing 5 mgsaxagliptin (as hydrochloride) immediate release and 1000 mg metformin hydrochloride modified release.
  • KOMBIGLYZE XR 2.5/1000 tablets containing 2.5 mg saxagliptin (as hydrochloride) immediate release and 1000 mg metformin hydrochloride modified release.

  • KOMBIGLYZE XR is indicated as an adjunct to healthy eating andphysical activity to improve glycaemic management inadults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin isappropriate.

For the latest PBS indications for KOMBIGLYZE XRplease 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.

  • KOMBIGLYZE XR should be taken with or after food.
  • The dosage of diabetes therapy with KOMBIGLYZE XR should be individualised based on the person’s current regimen, effectiveness, and tolerability while not exceeding the maximum recommended dose of saxagliptin 5 mg and metformin extended release 2000 mg.
  • KOMBIGLYZE XR should generally be administered once daily with the evening meal, with gradual dose titration to reduce the gastrointestinal side effects associated with metformin.
  • Individuals should be informed that KOMBIGLYZE XR tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients of KOMBIGLYZE XR will be eliminated in the faeces as a soft, hydrated mass that may resemble the original tablet.
  • As add on combination therapy: If therapy with a combination tablet containing saxagliptin and metformin is considered appropriate, the recommended dose of saxagliptin is 5 mg once daily. The recommended starting dose of metformin extended release is 500 mg once daily, which can be titrated to 2000 mg once daily. The maximum dose of KOMBIGLYZE XR is saxagliptin 5 mg/metformin extended release 2000 mg taken as two 2.5 mg/1000 mg tablets once daily.
  • As initial combination therapy: The recommended starting doses of KOMBIGLYZE XR when used as initial combination therapy is one 5 mg/500 mg tablet once daily. Individuals with inadequate glycaemic management on this startingdose should further have their metformin dose increased to 5 mg/1000 mg once daily or two 2.5mg/1000 mg tablets once daily as appropriate.
  • Renal impairment: Renal function should be assessed prior to initiation of KOMBIGLYZE XR and periodically thereafter. Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of KOMBIGLYZE XR in those with eGFR < 60 mL/min/1.73m2.

-Mild renal impairment (eGFR 60-89 mL/min/1.73m2): No dosage adjustment is required for those with mild renal impairment. (eGFR 60-89 mL/min/1.73 m2 (by Modified Diet in Renal Disease [MDRD] eGFR equation).

-Moderate renal impairment (eGFR 30-59 mL/min/1.73 m2): No dosage adjustment is required for individuals with eGFR ≥ 45 mL/min/1.73 m2.

-It is not recommended to initiate treatment with KOMBIGLYZE XR in those with eGFR <45 mL/min/1.73 m2. If during treatment eGFR falls to levels persistently below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy and limit the maximum dose of KOMBIGLYZE XR to 2.5 mg/1000 mg once daily.

-Severe Renal Impairment(eGFR < 30 mL/min/1.73 m2): KOMBIGLYZE XR is contraindicated in individuals with severe renal impairment (eGFR < 30mL/min/1.73 m2).

  • Hepatic impairment: Since impaired hepatic function has been associated with some cases of lactic acidosis in those taking metformin, KOMBIGLYZE XR should be avoided with clinical or laboratory evidence of hepatic impairment.

  • Saxagliptin and metformin are eliminated in part by the kidney, and therefore, because the elderly are more likely to have decreased renal function, KOMBIGLYZE XR should be used with caution as age increases.

  • Hypersensitivity to the active substances or to any of the excipients, or a history of any serious hypersensitivity reaction, including anaphylactic reaction and angioedema, to any dipeptidyl peptidase 4 (DPP4) inhibitor.
  • Metabolic acidosis: Acute or chronic metabolic acidosis, including lactic acidosis or diabeticketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
  • Diabetic pre-coma
  • Severe renal impairment (eGFR < 30 mL/min/1.73 m2)
  • Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock, or intravascular administration of iodinated contrast agents.
  • Acute or chronic disease which may cause tissue hypoxia such as: cardiac or respiratory failure, pulmonary embolism, recent myocardial infarction, shock, 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.
  • Lactation

  • General: KOMBIGLYZE XR should not be used in individuals with type 1 diabetes mellitus. KOMBIGLYZE XR has not been studied in combination with GLP-agonists.
  • 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.

-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 KOMBIGLYZE XR.

  • Monitoring of renal function: Renal function should be confirmed before initiation of KOMBIGLYZE XR 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 individuals.
    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.

  • 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 patients on KOMBIGLYZE XRand 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.

-During post marketing experience the following adverse reactions have been reported with use of saxagliptin: serious hypersensitivity reactions, including anaphylaxis and angioedema. Becausethese reactions are reported voluntarily from a population of uncertain size, it is not possible toreliably estimate their frequency. If a serious hypersensitivity reaction to saxagliptin is suspected, discontinue KOMBIGLYZE XR, assess for other potential causes for the event, and institute alternative treatment for diabetes.

-Pancreatitis: During post marketing experience, there have been spontaneously reported adverse reactions ofacute pancreatitis. Individualss should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, KOMBIGLYZE XR should be discontinued.

Note:Diabetes MedsCheck with counselling on side effect profile and referral to healthcare team if suspected.

Bullous pemphigoid: post-marketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell individuals to reportdevelopment of blisters or erosions while receiving KOMBIGLYZE XR. If bullous pemphigoid issuspected, KOMBIGLYZE XR should be discontinued and referral to a dermatologist should beconsidered for diagnosis and appropriate treatment
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 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 saxagliptin.
Note: Diabetes MedsCheck with counselling on side effect profile and referral to healthcare team if suspected.

  • The results of bioequivalence studies in healthy subjects demonstrated that KOMBIGLYZE XRcombination tablets are bioequivalent to coadministration of corresponding doses of saxagliptin and metformin hydrochloride modified release as individual tablets.
  • The following statements reflect the pharmacokinetic properties of the individual active substancesof KOMBIGLYZE XR.
    Saxagliptin: The pharmacokinetics of saxagliptin have been extensively characterised in healthy subjects andpeople with type 2 diabetes. Saxagliptin was rapidly absorbed after oral administration, withmaximum saxagliptin plasma concentrations (Cmax) usually attained within two hours afteradministration in the fasted state. Following a single oral dose of 5 mg saxagliptin to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin was 2.5 hours, and the mean t1/2 value for plasma DPP-4 inhibition was26.9 hours. The inhibition of plasma DPP-4 activity by saxagliptin for at least 24 hours after oraladministration is due to high potency, high affinity, and extended binding to the active site. Appreciable accumulation was observed with repeated once-daily dosing at any dose level. Nodose- and time-dependence was observed in the clearance of saxagliptin and its major metaboliteover 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 mg to 400 mg.
    Metformin hydrochloride: Metformin extended release Cmax is achieved with a median value of 7 hours. The extent ofmetformin absorption from the metformin extended-release tablet is increased by approximately50% when given with food. At steady state, the AUC and Cmax are less than dose proportional formetformin extended release within the range of 500 to 2000 mg. After repeated administration ofmetformin extended-release, metformin did not accumulate in plasma. Metformin is excretedunchanged in the urine and does not undergo hepatic metabolism.

  • Saxagliptin: Based on food effects studies, saxagliptin may be administered with or without food. However, inpivotal efficacy and safety studies saxagliptin was generally taken prior to the morning meal. Theamount of saxagliptin absorbed following an oral dose is at least 75%. The absolute oralbioavailability of saxagliptin is approximately 50% (90% CI of 48-53%). Food had relativelymodest effects on the pharmacokinetics of saxagliptin in healthy subjects.
  • Metformin hydrochloride: Following a single oral dose of metformin extended release, Cmax is achieved with a median valueof 7 hours and a range of 4 to 8 hours. Both high and low-fat mealshad the same effect on the pharmacokinetics of metformin extended release.

  • Saxagliptin: The in vitro protein binding of saxagliptin and its major metabolite in human serum is belowmeasurable levels. Thus, changes in blood protein levels in various disease states (e.g., renal orhepatic impairment) are not expected to alter the disposition of saxagliptin.
  • Metformin hydrochloride: Distribution studies with extended-release metformin have not been conducted; however, theapparent volume of distribution (V/F) of metformin following single oral doses of immediaterelease metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasmaproteins, in contrast to sulfonylureas, which are more than 90% protein bound.

  • Saxagliptin: The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). Themajor metabolite of saxagliptin is also a reversible, competitive DPP-4 inhibitor, half as potent assaxagliptin. It also demonstrates selectivity for DPP-4 versus other DPP enzymes, with greater than163-fold selectivity over DPP-8 and DPP-9.
  • Metformin hydrochloride: Intravenous single-dose studies in normal subjects demonstrate that metformin is excretedunchanged in the urine and does not undergo hepatic metabolism (no metabolites have beenidentified in humans) or biliary excretion.

  • Saxagliptin: Saxagliptin is eliminated by both renal and hepatic pathways. The average renal clearance of saxagliptin (~230mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min),suggesting some active renal excretion. For the major metabolite, renal clearance values werecomparable to estimated glomerular filtration rate. A total of 22% of the administered radioactivitywas recovered in faeces representing the fraction of the saxagliptin dose excreted in bile and/orunabsorbed drug from the gastrointestinal tract.
  • Metformin hydrochloride: Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates thattubular secretion is the major route of metformin elimination. Following oral administration,approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours. When renal function is impaired, renal clearance is decreased in proportion to that ofcreatinine and thus the elimination half-life is prolonged, leading to increased levels of metforminin plasma.