New metformin fixed-dose combinations PBS listed

Two of the four new combinations contain the metformin extended-release (XR) formulation. In clinical trials metformin XR has been shown to have efficacy comparable to that of immediate-release (IR) metformin.^{1, 2}

In addition to comparable efficacy it is claimed that the metformin XR formulation results in fewer GI side effects than metformin IR.^2-4 Metformin XR may therefore be an option for patients who experience an unacceptable level of GI side effects with metformin IR.^{2, 4, 5}

However, a retrospective cohort study investigating relative GI tolerability only showed a lower incidence of GI side effects for patients who had been switched from metformin IR to metformin XR after GI upset, or for treatment-naïve patients who had been started on metformin XR.⁶ The study did not show any difference overall in GI adverse events between groups given IR or XR formulations.⁶

In addition to fewer GI side effects, use of metformin XR is purported to result in improved adherence through once-daily dosing^{3, 4} compared with metformin IR, which may have 2–3 times daily dosing. A population-based study demonstrated improved adherence in patients taking XR compared with IR formulations but it is unclear from this small observational study whether the improvement in adherence was attributable to once-daily dosing or to reduced side effects.⁵

Fixed-dose combination products

As with all FDC products, stabilise patients on the individual components taken separately before switching to the combination product.

While improved adherence through simplified dosing is a potential benefit of FDC products, other issues may impact efficacy and safety. There is a risk that use of a once-daily FDC product may result in inadvertent double dosing through patient confusion over which products the FDC replaces and/or because people who are used to multiple daily dosing may mistakenly take more doses than prescribed. In addition, as with all FDC products, there are limited options for dose adjustment.

All four products are subject to the same PBS restrictions for subsidy, as follows.

Authority Required (STREAMLINED)
Diabetes mellitus type 2

Clinical criteria:

• Patient must have, or have had, an HbA_1c measurement > 7% despite treatment with metformin; OR
• Patient must have, or have had, where HbA_1c measurement is clinically inappropriate, blood glucose levels > 10 mmol/L in more than 20% of tests over a 2-week period despite treatment with metformin.
  The date and level of the qualifying HbA_1c measurement must be, or must have been, documented in the patient's medical records at the time treatment with a dipeptidyl peptidase 4 inhibitor (gliptin), a thiazolidinedione (glitazone), a glucagon‐like peptide‐1-related (GLP-1-related) drug or a sodium–glucose co-transporter-2 (SGLT2) inhibitor is initiated.
• The HbA_1c must be no more than 4 months old at the time treatment with a gliptin, a glitazone, a GLP‐1-related drug or an SGLT2 inhibitor was initiated.
• Blood glucose monitoring may be used as an alternative assessment to HbA_1c levels in the following circumstances:
  a) a clinical condition with reduced red blood cell survival, including haemolytic anaemias and haemoglobinopathies; and/or
  b) red cell transfusion within the previous 3 months.
  The results of the blood glucose monitoring, which must be no more than 4 months old at the time of initiation of treatment with a gliptin, a glitazone, a GLP‐1-related drug or an SGLT2 inhibitor, must be documented in the patient's medical records.
• A patient whose diabetes was previously demonstrated unable to be controlled with metformin does not need to requalify on this criterion before being eligible for PBS‐subsidised treatment with this fixed-dose combination.

Authority required (STREAMLINED)
Diabetes mellitus type 2
Treatment Phase: Continuing

Clinical criteria:

Patient must have previously received, and been stabilised on, a PBS‐subsidised regimen of oral diabetic medicines which includes metformin and gliptin specific to the combination product.

Note:

The fixed-dose combination tablets are not PBS subsidised for use in combination with a sulfonylurea (triple oral therapy), as initial therapy or in combination with a thiazolidinedione (glitazone), a GLP-1-related drug or an SGLT2 inhibitor.