Linagliptin with metformin hydrochloride, tablets, 2.5 mg/500 mg, 2.5 mg/850 mg and 2.5 mg/1000 mg, Trajentamet® - March 2013
Public Summary Document
Product: Linagliptin with metformin hydrochloride, tablets, 2.5 mg/500 mg, 2.5 mg/850 mg and
2.5 mg/1000 mg, Trajentamet®
Sponsor: Boehringer Ingelheim Pty Ltd
Date of PBAC Consideration: March 2013
1. Purpose of Application
The submission requested an Authority required (STREAMLINED) listing for treatment of type 2 diabetes mellitus (T2DM) in a patient whose HbA1c is greater than 7% prior to initiation of a gliptin, glitazone or a glucagon-like peptide-1 despite treatment with metformin and where a combination of metformin and a sulfonylurea is contraindicated or not tolerated.
The PBAC had not previously considered this fixed dose combination (FDC) product. Linagliptin tablets and metformin tablets are both currently TGA registered and PBS listed.
3. Registration Status
The submission was considered under the TGA/PBAC parallel process. At the time of PBAC consideration, the Clinical Evaluation Report and TGA Delegate’s overview were available.
Linagliptin with metformin was registered by the TGA on 21 May 2013.
4. Listing Requested and PBAC’s View
Authority required (STREAMLINED)
Type 2 diabetes in a patient whose HbA1c is greater than 7% prior to initiation of a dipeptidyl peptidase 4 inhibitor (gliptin), a thiazolidinedione (glitazone) or a glucagon-like peptide-1 despite treatment with metformin and where a combination of metformin and a sulfonylurea is contraindicated or not tolerated.
The date and level of the qualifying HbA1c must be documented in the patient's medical records at the time treatment with a gliptin, a glitazone or a glucagon-like peptide-1 is initiated. The HbA1c must be no more than 4 months old at the time treatment with a gliptin, a glitazone or a glucagon-like peptide-1 is initiated.
Blood glucose monitoring may be used as an alternative assessment to HbA1c levels in the following circumstances:
(a) clinical conditions with reduced red blood cell survival, including haemolytic anaemias and haemoglobinopathies; and/or
(b) red cell transfusion within the previous 3 months.
A patient in these circumstances will be eligible for treatment where blood glucose monitoring over a 2 week period shows blood glucose levels greater than 10 mmol per L in more than 20% of tests. The results of this blood glucose monitoring, which must be no more than 4 months old at the time of initiation of treatment with a gliptin, a glitazone or a glucagon-like peptide-1, must be documented in the patient's medical records.
Authority required (STREAMLINED)
Continuation of therapy in type 2 diabetes mellitus in a patient who has previously received and been stabilised on a PBS-subsidised regimen of oral diabetic medicines which includes metformin and linagliptin.
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Linagliptin/metformin FDC will provide a treatment alternative to concurrent use of linagliptin and metformin for T2DM patients with inadequate glycaemic control despite using metformin alone. There are currently three other FDCs involving a dipeptidyl peptidase-4 (DPP-4) inhibitor or a thiazolidinedione in combination with metformin for the treatment of T2DM listed on the PBS:
- rosiglitazone/metformin FDC;
- sitagliptin/metformin FDC; and
- vildagliptin/metformin FDC.
The submission presented a clinical management algorithm which was based on treatment guidelines published by Diabetes Australia and the Royal Australian College of General Practitioners.
The submission proposed that the listing of the linagliptin/metformin FDC on the PBS would be prescribed to patients who would otherwise be prescribed linagliptin and metformin as separate tablets.
The submission nominated linagliptin and metformin constituent tablets as the comparator. The PBAC accepted this as the appropriate comparator.
For PBAC’s view, see Recommendation and Reasons.
7. Clinical Trials
The submission presented four randomised pharmacokinetics trials comparing the bioavailability of linagliptin/metformin FDC with linagliptin and metformin constituent tablets (1218.47, 1288.2, 1288.3 and 1288.1), and one randomised controlled trial comparing linagliptin and metformin taken concomitantly with metformin or linagliptin monotherapy, and placebo in patients with type 2 diabetes mellitus (1218.46).
Study 1218.47 was a single dose crossover study aimed at examining the relative bioavailability of a pilot formulation of linagliptin 2.5 mg/metformin 1,000 mg FDC compared to the free combination of linagliptin 5 mg and metformin 1,000 mg.
Studies 1288.2, 1288.3 and 1288.1 were single dose crossover studies that evaluated whether the proposed FDC formulations linagliptin 2.5 mg/metformin 500 mg, linagliptin 2.5 mg/metformin 850 mg and linagliptin 2.5 mg/metformin 1,000 mg were bioequivalent to the respective free dose combinations of linagliptin 2.5 mg and metformin 500 mg/850 mg/1,000 mg.
The primary endpoints for these pharmacokinetics studies were AUC0-72h and Cmax for linagliptin and AUC0-∞ and Cmax for metformin. The acceptable range for bioequivalence was the 90% confidence interval of the geometric mean ratios between 80% and 125%.
Study 1218.46 assessed the efficacy of concomitant linagliptin 2.5 mg and metformin 500 mg (bid) and linagliptin 2.5 mg and metformin 1,000 mg (bid) compared with linagliptin 5 mg monotherapy (qd) and metformin 500 mg/1,000 mg monotherapy (bid).
The bioequivalence studies were unpublished internal study reports. Publication details of study 1218.46 are presented in the table below.
Haak T et al 2012
Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes: a randomized, double-blind, placebo-controlled study
Diabetes, Obesity & Metabolism 2012; 14(6), 565-
For PBAC’s view, see Recommendation and Reasons.
8. Results of Trials
Bioequivalence was demonstrated with linagliptin 2.5 mg/metformin 500 mg FDC, linagliptin 2.5 mg/metformin 850 mg FDC, and linagliptin 2.5 mg/metformin 1,000 mg FDC compared to the use of individual tablets, as the 90% confidence intervals for all parameters were within the bioequivalence acceptable range of 80% to 125%.
Trial 1218.46 only assessed the efficacy of the free dose combination of concomitant linagliptin and metformin against monotherapy. The primary outcome was the change in HbA1c from baseline to week 24. The primary results are presented in the table below.
Results of HbA1c from baseline to 24 weeks of the randomised trial
Metformin alone (500 or 1000mg)
adjusted mean (SE)
Linagliptin alone 5mga
Adjusted mean difference
M 500 mg bid
-0.6 (-0.8, -0.4)
M 500 mg bid
-0.8 (-1.0, -0.5)
M 1,000 mg bid
-0.5 (-0.7, -0.3)
M 1,000 mg bid
-1.1 (-1.5, -0.9)
Source: Haak 2012, Table 2
Abbreviations: SE = standard error, bid=twice daily
aLinagliptin was administered as 2.5mg twice daily when combined with metformin 500mg or 1,000mg
The results of 1218.46 demonstrated that linagliptin taken in combination with metformin was superior to linagliptin alone, and metformin alone based on the change in HbA1c from baseline at week 24.
The PBAC recalled it had previously accepted the relevance of the change in mean HbA1c as a surrogate outcome for assessing efficacy1. The PBAC noted that linagliptin is currently reimbursed for use as a dual therapy with metformin and/or sulfonylurea but it is not registered or reimbursed for use as a monotherapy. The PBAC further noted that trial participants included treatment naïve patients which was not representative of the intended population for the linagliptin/metformin FDC. These study characteristics reduced the applicability of this trial for assessing the FDC.
There were no differences between the adverse events (AE) reported for subjects who received single tablets compared with the linagliptin/metformin FDC in trials 1288.2, 1288.3 and 1288.1. Only trial 1288.1 indicated a greater number of patients experiencing severe AEs whilst receiving the FDC compared to the single tablets.
The most commonly experienced treatment-related AEs in the single dose trials were headache, followed by nasopharyngitis, diarrhoea or vomiting, consistent with the safety profile described in the Product Information.
The proportion of subjects reporting any AE in trial 1218.46 was similar in the placebo arm (54.2%) compared with the linagliptin and/or metformin arms (49.0%-56.6%). The proportion of subjects exhibiting SAE was low, ranging from 1.4% in subjects randomised to placebo and both linagliptin and metformin study arms, to 4.1% in subjects randomised to metformin 1,000 mg bid.
The PBAC considered that the submission failed to address the issue of the difficulty of managing two sets of adverse events with the combined drugs in the FDC since both of the medications would need to be stopped if the patient is required to discontinue the FDC. In addition, since trial 1218.46 included treatment naïve patients, the trial participants may have presented with less advanced disease and therefore less likely to present with adverse events.
9. Clinical Claim
The submission described linagliptin/metformin FDC as bioequivalent with respect to both effectiveness and safety when compared with linagliptin and metformin taken separately.
The PBAC considered the submission’s claim that linagliptin/metformin FDC as bioequivalent to linagliptin and metformin taken separately, was adequately supported. However, noting that the final TGA registration was not yet available, the PBAC also noted that the final assessment of acceptable bioequivalence was a matter for the TGA.
The PBAC considered that claims regarding the effectiveness and safety of the FDC compared to the constituent tablets could not be determined from the studies provided, as they were single dose studies and did not directly assess a course of multi-dose treatment over time.
The submission claimed that concomitant linagliptin and metformin was significantly more effective than linagliptin or metformin single tablets taken as monotherapy alone based on the change in HbA1c from baseline at week 24. The PBAC accepted that the submission provided adequate evidence (Study 1218.46) that there is an additional clinical effect compared to metformin alone, in terms of reduction in HbA1c.
10. Economic Analysis
The submission presented a cost-minimisation analysis based on the bioequivalence of linagliptin/metformin FDC compared to the constituent drugs.
The equi-effective doses were estimated as follows:
- Linagliptin in the FDC (2.5 mg twice daily) is the same as linagliptin single tablets (5 mg once daily)
- The daily dose of metformin in the linagliptin 2.5 mg/metformin 500 mg FDC tablet is 1,000 mg. It is assumed that patients prescribed the FDC would have previously taken a single tablet of 1,000 mg prior to switching to the FDC.
- The daily dose of metformin in the linagliptin 2.5 mg/metformin 850 mg FDC tablet is 1,700 mg, with the assumption that patients would have previously received two single tablets of 850 mg metformin.
- The daily dose of metformin for patients taking the linagliptin 2.5 mg/metformin 1,000 mg FDC tablet is 2,000 mg, with patients previously receiving two single tablets of 1,000 mg metformin
The proposed price of the linagliptin/metformin FDC was calculated using the equivalent reimbursed prices for the linagliptin and metformin components of the combination tablet.
The PBAC accepted the estimated equi-effectiveness doses and considered the cost-minimisation analysis reasonable based on the submission’s claim of bioequivalence.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of prescriptions per year of linagliptin/metformin FDC (all strengths) to be between 100,000 and 200,000 in Year 5. The submission estimated a greater reduction (while within the same range) in the number of prescriptions for the constituent products and other gliptin/metformin FDCs. The net costs to the PBS/RPBS and the Government (taking into account cost savings to the MBS) were both estimated in the submission to be less than $10 million in Year 5.
The PBAC noted the submission’s claim that patients likely to be prescribed the linagliptin/metformin FDC, would be patients switching from a current combination treatment of the components, as well as a small number of patients switching from existing listed gliptin/metformin FDCs. The estimated cost savings to the MBS were based on a reduction in liver function tests from patients switching to the linagliptin/metformin FDC from the vildagliptin/metformin FDC. The PBAC considered that this cost saving was uncertain as the assumption that patients will switch from vildagliptin/metformin FDC to linagliptin/metformin FDC was unsupported.
The PBAC considered that the submission’s estimate of usage was uncertain and was a likely underestimate on the basis of the potential for leakage beyond the requested PBS population for the linagliptin/metformin FDC, from third line use, to first line use in patients unable to tolerate or contraindicated to sulfonylurea therapy. In addition, the PBAC noted experience with other PBS listed gliptin/metformin FDCs indicated that there is potential for higher uptake than anticipated, and that a proportional decrease in the proposed substituted therapies, may not eventuate in practice.
The PBAC noted the potential for other use outside of the PBS subsidy criteria, including as triple oral therapy with sulphonylurea, metformin and a gliptin, and a proportion of patients where a gliptin is added to metformin, and where the patient does not have a contraindication or intolerance to a sulphonylurea.
The PBAC noted the following concerns with the linagliptin/metformin FDC with respect to completely meeting the guidelines for FDCs:
- Criterion (f) requires that the combination not encourage or result in an inappropriate increase in overall utilisation of the components, nor inappropriate use of one or both components in specific patient groups. The PBAC considered that there is a risk that linagliptin/metformin FDC may be used earlier in the treatment algorithm than specified in the PBS restriction based on sources of information provided by the DUSC relating to predicted versus actual use of combination drugs.
- Criterion (g) requires that the combination product not result in inappropriate dosing of either component, nor contain components which require individual dose titration. The PBAC considered that there was risk of inappropriate dosing with linagliptin/metformin FDC as the metformin component requires titration.
- Criterion (h) requires that the combination product not result in unnecessary proliferation of product and/or dose forms. The PBAC was not convinced of a pressing clinical need for a linagliptin/metformin FDC as there are currently two PBS listed gliptin/metformin FDCs.
12. Recommendation and Reasons
The PBAC deferred consideration of this submission pending finalisation of the TGA registration process, particularly the final indication, and further consideration of predicted utilisation and financial implications based on the Drug Utilisation Sub-Committee (DUSC) utilisation analysis.
The PBAC noted the requested restriction was consistent with current restrictions for other gliptin with metformin FDC products.
The PBAC also noted a PBS post market review (PMR) of products used in the management of diabetes was currently underway. It noted that one of the terms of reference of this review was to describe the utilisation and patterns of treatment of PBS listed drugs for type 2 diabetes mellitus, and to compare these with PBS restrictions. Hence, the findings of this review may impact the PBS restrictions for medicines for the treatment of diabetes mellitus.
The PBAC noted a preliminary report from the Drug Utilisation Sub-Committee from its February 2013 meeting on the utilisation of gliptins and gliptin-metformin FDCs. The DUSC utilisation analysis, that had been provided to sponsors for comment, suggested that at least 30% of current use of gliptins and gliptin-FDCS is not consistent with existing restrictions. The PBAC considered that new products of this class would need to be assessed in this context.
The PBAC considered that it would be essential to consider the final report from DUSC before defining the appropriate restrictions for linagliptin/metformin as a new FDC. There may also be implications for the current restrictions for existing gliptin/metformin FDCs following consideration of the DUSC report. If there is in fact evidence to support what appears to be the evolving clinical use of gliptins higher up the treatment algorithm, including as an alternative to sulfonylureas as second line therapy, then this use is not consistent with the cost-effective use that was previously accepted by the PBAC for gliptins or gliptin/metformin FDCs. The PBAC also considered that the addition of another FDC of gliptin with metformin could promote the current rapid growth in utilisation of gliptins.
The PBAC noted that the final report from DUSC would be provided to PBAC for consideration at its Special meeting in April 2013, and agreed to re-consider the PBS-listing of linagliptin/metformin FDC at that meeting.
The application was subsequently considered at the April 2013 PBAC Special PBAC meeting and the outcome will be published at a later date.
Based on the DUSC utilisation analysis, the PBAC considered that the submission’s estimates of utilisation and financial implications were highly uncertain and likely to be significantly underestimated, should the linagliptin/metformin FDC be used in the same way as the currently PBS listed DPP-4 inhibitor (gliptin)/metformin FDCs.
The PBAC agreed it would be reasonable to extrapolate the risk of use outside the restriction seen for currently listed gliptin/metformin FDCs as it would also apply to linagliptin/metformin FDC, should the PBS indication be approved as proposed.
The PBAC noted that whilst the requested listing of linagliptin/metformin FDC on the PBS would allow prescribing to patients who would otherwise be prescribed linagliptin and metformin as separate tablets, preliminary results from the DUSC utilisation review suggest gliptins are being used earlier in the treatment algorithm.
The PBAC considered the submission’s cost minimisation approach based on bioequivalence of the FDC against the individual components to be reasonable.
The PBAC considered the nominated comparator was appropriate and consistent with comparators previously accepted for other gliptin/metformin FDCs. However, the PBAC also noted that the two currently PBS-listed gliptin/metformin FDCs may also be considered as comparators.
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia. It considers submissions in this context. A PBAC decision not to recommend listing or not to recommend changing a listing does not represent a final PBAC view about the merits of the medicine. A company can resubmit to the PBAC or seek independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor had no further comment.
1 PBAC (March 2009) Sitagliptin with metformin FDC, extract of March 2009 PBAC minutes.
PBAC (Nov 2010) Vildagliptin with metformin FDC, extract of November 2010 PBAC minutes.