Pharmacy Diabetes

Fixed_dose-Advandamet

Rosiglitazone (as maleate) and metformin hydrochloride

  • Avandamet film coated tablets contain 2 mg/500 mg, 4 mg/500 mg, 2 mg/1000 mg or 4 mg/1000 mg rosiglitazone (as maleate) and metformin hydrochloride as the active ingredients.

  • AVANDAMET is indicated as an adjunct to heathy eating and physical activity to improve glycaemic management in individuals with type 2 diabetes mellitus (non-insulin dependent diabetes mellitus), as dual combination therapy in those who are already treated with rosiglitazone and metformin in combination, or who are inadequately treated on metformin or rosiglitazone alone.

For the latest PBS indications for AVANDAMET please see
https://www.pbs.gov.au/pbs/industry/listing/elements/pbac-meetings/psd/2007-11/pbac-psd-rosiglitazone-nov07

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.

  • The use of AVANDAMET is not recommended in those with known ischaemic heart disease, particularly those taking nitrates. Rosiglitazone has been shown to be associated with an increased risk of myocardial ischaemia (angina, infarction) in pooled short-term clinical studies compared to combined active/placebo control (2.00% versus 1.53%, respectively), particularly in those who needed several antidiabetic drugs or nitrates
  • Due to the metformin component,
  • AVANDAMET should be given twice a day. Taking AVANDAMET with or just after food may reduce gastrointestinal symptoms associated with the metformin component.
  • The usual starting daily dose of AVANDAMET is 4 mg/1000 mg. The daily dose of rosiglitazone-metformin may be increased to maintain the individual's glycaemic management.
  • Dose titration should be to a maximum recommended total daily dose of 8 mg rosiglitazone/2000 mg metformin.
  • Only one strength of AVANDAMET should be prescribed and used at any one time, and treatment with other metformin containing products should be discontinued. There is potential risk of accidental overdosing presented by the continuance of previously prescribed metformin containing products.
  • Dosage Recommendations:
    - For those whose diabetes is inadequately managed on metformin monotherapy: the usual starting dose of AVANDAMET is 4 mg rosiglitazone (total daily dose) plus the dose of metformin already being taken.
    - For those whose diabetes is inadequately managed on rosiglitazone monotherapy: the usual starting dose of AVANDAMET is 1000 mg metformin (total daily dose) plus the dose of rosiglitazone already being taken.
    - When switching from combination therapy of rosiglitazone plus metformin as separate tablets: the usual starting dose of AVANDAMET is the dose of rosiglitazone and metformin already being taken.
    - A slow increase of dose may reduce GI side effects (largely due to metformin); dose escalation should be by increments of 4mg/day rosiglitazone and/or 1000mg/day metformin, to a maximum recommended total daily dose of 8mg/2000mg. The interval for dose adjustment should be individualised to an individual’s response (person centred care). The full effect of dose adjustment may not be seen for six to eight weeks for the rosiglitazone component and one to two weeks for the metformin component.
  • Renal impairment: Limited data are available in individuals with severe renal insufficiency being treated with rosiglitazone. As metformin is excreted by the kidney, creatinine clearance levels should be determined before initiating treatment with AVANDAMET and regularly thereafter. AVANDAMET should not be used in those with renal dysfunction (creatinine clearance < 60 mL/min). Special caution should be exercised in those likely to have renal impairment, e.g. the elderly, or in situations where renal function may become impaired, e.g. dehydration, severe infection, or shock.
  • Hepatic impairment: In individuals with mild hepatic impairment (Child-Pugh A, scores of 6 or less) no dose adjustment of rosiglitazone is required. However, due to limited experience with both rosiglitazone and metformin, AVANDAMET is not recommended in those with hepatic impairment.

  • As metformin is excreted via the kidney, the initial and maintenance dosing of AVANDAMET should be conservative in the elderly due to the potential for decreased renal function in this population. Any dosage adjustment should be based on renal function, which should be monitored.

  • Previous history of hypersensitivity to rosiglitazone, metformin, or any of the listed excipients.
  • Due to the metformin component of AVANDAMET it is contraindicated in diabetic ketoacidosis or pre-coma and renal failure (creatinine clearance < 60 mL/min).
  • AVANDAMET is contraindicated in individuals with, type 1 diabetes that is uncomplicated and well-regulated on insulin; diabetes mellitus regulated by healthy eating alone; acute complications of diabetes mellitus such as metabolic acidosis, coma, infection, gangrene, or during or immediately following surgery where insulin is essential.
  • AVANDAMET should be temporarily withheld in those undergoing radiological studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.
  • Risk of lactic acidosis: Because of the danger of lactic acidosis, AVANDAMET should not be used in the presence of the following conditions: diminished renal function; cardiovascular disease (e.g. coronary insufficiency, myocardial infarction and hypertension); conditions that may be associated with tissue hypoxia (e.g. gangrene, circulatory shock, acute significant blood loss); pulmonary embolism; severe hepatic dysfunction; pancreatitis; excessive alcohol intake; concomitant use of diuretics.
  • Initiation of rosiglitazone combination regimens (like other thiazolidinediones combination regimens) is contraindicated in those with NYHA Class III and IV heart failure (See use of rosiglitazone combination regimens is contraindicated in those:
    - with NYHA Class I to IV heart failure or history of cardiac failure
    - experiencing an Acute Coronary Syndrome (unstable angina, NSTEMI and STEMI)

  • AVANDAMET is not a substitute for insulin in those requiring insulin. GALVUMET should not be used in individuals with T1D or for the treatment of diabetic ketoacidosis.
  • Because of improving insulin sensitivity, AVANDAMET treatment in premenopausal anovulatory patients with insulin resistance (e.g., individuals with polycystic ovary syndrome) may result in resumption of ovulation. These individuals may be at risk of pregnancy.
    Note: Diabetes MedsCheck with counselling on the increased risk.
  • 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.
  • Cardiac failure: An increased incidence of cardiac failure has been observed in clinical trials when thiazolidinediones are used in combination with insulin. Insulin and rosiglitazone are both associated with fluid retention, concomitant administration may increase the risk of oedema and could increase the risk of ischaemic heart disease. AVANDAMET should not be initiated with those on insulin. Insulin should not be initiated with those on AVANDAMET. These combinations are not approved. Long term studies on morbidity (including cardiovascular effects) and mortality outcomes are not yet available. AVANDAMET should not be prescribed to lower cardiovascular risk.
  • Congestive Heart Failure: Rosiglitazone, like other thiazolidinediones can cause or exacerbate congestive heart failure (CHF) in some individuals. After initiation of AVANDAMET, and after dose increases, individuals should be monitored for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnoea, and/or oedema). If these signs and symptoms develop and CHF is diagnosed AVANDAMET should be discontinued.
    Note: Diabetes MedsCheck with counselling on side effect profile with referral to healthcare team 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 if suspected.
    - 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 individuals. 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 individuals on AVANDANET 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.
    - 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.
    • Rosiglitazone
    - Myocardial Ischaemia: Rosiglitazone has been shown to be associated with an increased risk of myocardial ischaemia (angina, infarction) in pooled short-term clinical studies (see below). AVANDAMET is therefore not recommended for individuals with known ischaemic heart disease (IHD), particularly those who are currently being treated with nitrates.
    Note: Diabetes MedsCheck with counselling on of side effect profile with referral to healthcare team for annual cycle of care.
    - Fluid Retention: Fluid retention may occur. Signs and symptoms of fluid retention, including weight gain should be monitored. The possible contribution of fluid retention to weight gain should be individually assessed.
    Note: Diabetes MedsCheck with referral to appropriate to healthcare team if observed.- Effects on Bone: In a 4-to-6-year study of glycaemic management with monotherapy in recently diagnosed individuals with type 2 diabetes mellitus, an increased incidence of bone fracture was noted in females taking rosiglitazone (9.3%, 2.7 patients per 100 patient years) vs metformin (5.1%, 1.5 individuals per 100 patient years) or glibenclamide (3.5%, 1.3 individualls per 100 patient years). Most of the fractures in the females who received rosiglitazone were reported in the upper arm, hand and foot. Other trials suggest that this risk may also apply to men, although the risk of fracture among women appears higher than that among men. The risk of fracture should be considered in the care of those treated with rosiglitazone, and attention should be given to assessing and maintaining bone health according to current standards of care.
    Note: Diabetes MedsCheck with counselling on side effect profile with referral to healthcare team for annual cycle of care.
    - Eye Disorder: Very rare post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visual acuity have been reported with thiazolidinediones. Many of these reported concurrent peripheral oedema. In some cases, the visual events resolved or improved following discontinuation of the drug. Prescribers should be alert to the possibility of macular oedema if patients report disturbances in visual acuity.

    Note: Diabetes MedsCheck with counselling on side effect profile and referral to healthcare team for annual cycle of care.

  • AVANDAMET: In a bioequivalence and dose proportionality study of AVANDAMET 4 mg/500 mg, both the rosiglitazone component and the metformin component were bioequivalent to co-administered 4 mg rosiglitazone maleate tablet and 500 mg metformin hydrochloride tablet under fasted condition. In this study, dose proportionality of rosiglitazone in the combination formulations of 1 mg/500 mg and 4 mg/500 mg was demonstrated. A further bioequivalence and dose proportionality study demonstrated that the AVANDAMET combination formulation 4 mg/1000 mg was bioequivalent to two tablets of AVANDAMET 2 mg/500 mg. In addition, this study also established dose proportionality of rosiglitazone between the two combination tablet strengths of AVANDAMET 2 mg/1000 mg The pharmacokinetics of both the rosiglitazone component and the metformin component of AVANDAMET when taken with food were similar to the pharmacokinetics of rosiglitazone and metformin when administered concomitantly as separate tablets with food. and 4 mg/1000 mg.
  • Rosiglitazone maleate: Rosiglitazone is rapidly and completely absorbed after oral administration, with negligible first pass metabolism. Absolute bioavailability of rosiglitazone following both a 4 and an 8 mg oral dose is approximately 99%. Plasma concentrations of rosiglitazone peak at around 1 hour after dosing and are approximately dose proportional over the therapeutic dose range.
  • Metformin hydrochloride: After oral administration, metformin hydrochloride is absorbed along the entire gastrointestinal mucosa. Studies using single oral doses of metformin tablets indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an increase in elimination. At usual clinical doses and dosing schedules of metformin tablets, steady-state plasma concentrations are reached in24-48 hours and are generally less than 1 g/mL. During controlled clinical trials, maximum metformin plasma levels did not generally exceed 5 g/mL, even at maximum doses.

  • Rosiglitazone maleate: The volume of distribution of rosiglitazone is approximately 0.184 L/kg and total plasma clearance around 3 L/h in healthy volunteers. rosiglitazone is approximately 99.8% bound to plasma protein, primarily albumin. Concentration or age does not influence plasma protein binding of rosiglitazone. There is no evidence for unexpected accumulation of rosiglitazone after once daily or twice daily dosing.
  • Metformin hydrochloride: Metformin is not bound to plasma proteins.

  • Rosiglitazone maleate: Metabolism of rosiglitazone is extensive with no parent compound being excreted unchanged. The major routes of metabolism are N-demethylation and hydroxylation, followed by conjugation with sulphate and glucuronic acid. The metabolites of rosiglitazone are not considered to have any clinical relevance.
  • Metformin hydrochloride: Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism.

  • Rosiglitazone maleate: The terminal elimination half-life of rosiglitazone is approximately 3 to 4 hours. The major route of excretion is the urine with approximately two-thirds of the dose being eliminated by this route. Faecal elimination accounts for approximately 25% of dose.

For more detailed information on this product please consult the product information.

https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06887-3