Metformin and Sitagliptin, tablet, 1000mg/50mg, 1000mg/100mg, Janumet® XR - November 2013

Public Summary Document

Product: Metformin and Sitagliptin, tablet, 1000mg/50mg, 1000mg/100mg, Janumet® XR
Sponsor: Merck Sharp & Dohme (Australia) Pty Ltd
Date of PBAC Consideration: November 2013

1. Purpose of Application

The submission requested an Authority required (STREAMLINED) listing for treatment of type 2 diabetes mellitus (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.

This application was made under the TGA/PBAC parallel process. Subsequently, the product was included on the Australian Register of Therapeutic Goods (ARTG), prior to PBAC consideration.

2. Background

Metformin/sitagliptin fixed dose combinations (FDC) containing immediate release metformin are currently listed on the PBS. This is the first application for listing of a metformin/sitagliptin FDC containing XR metformin.

At the April 2013 special meeting, the PBAC recommended the listing of two other metformin/gliptin FDCs with a lower price and different restriction to the currently PBS subsidised metformin/gliptin FDCs (for more information, please visit the PBS website).

3. Registration Status

Metformin XR extended release (XR)/sitagliptin was TGA registered on 1 November 2013 and is indicated:

as initial therapy in patients with type 2 diabetes mellitus to improve glycaemic control when diet and exercise do not provide adequate glycaemic control, when dual sitagliptin and metformin therapy is appropriate (i.e. high initial HbA1c levels and poor prospects of response to monotherapy);
as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes mellitus inadequately controlled on sitagliptin or metformin alone or in patients already being treated with the combination of sitagliptin and metformin;
in combination with a sulfonylurea as an adjunct to diet and exercise in patients with type 2 diabetes mellitus when combination therapy with metformin and a sulfonylurea does not provide adequate glycaemic control;
as an adjunct to diet and exercise to improve glycaemic control in combination with insulin in patients with type 2 diabetes mellitus inadequately controlled on insulin and metformin or in patients already being treated with the combination of sitagliptin, metformin and insulin.

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 sitagliptin.

5. Clinical Place for the Proposed Therapy

The submission stated that metformin XR/sitagliptin FDC will provide a treatment alternative for patients who are currently treated with a) metformin XR and would have otherwise been prescribed metformin immediate release (IR)/sitagliptin FDC or metformin IR/vildagliptin FDC, or metformin XR in concomitant therapy with sitagliptin, or b) are currently controlled on metformin XR in combination with sitagliptin and would benefit from a FDC tablet containing metformin XR.

6. Comparator

The submission nominated the corresponding doses of the individual components of sitagliptin and metformin XR as comparator, on the basis that these are the therapies most likely to be substituted in practice. The submission also nominated metformin IR/sitagliptin FDC as the primary pricing comparator, as the cost of the IR FDC is less than the cost of the sum of the corresponding doses of sitagliptin and metformin XR.

The PBAC considered that this FDC would also replace other metformin/gliptin FDCs and that these other FDCs were also appropriate comparators.

7. Clinical Trials

The submission was based on three unpublished bioequivalence trials (Studies P147, n = 48; P300, n = 28; and P317, n = 64) in healthy adult patients without diabetes. Two pharmacokinetic studies (P164 and P165) provided further safety data.

Details of the trials presented in the submission are in the table below.

Trials and associated reports presented in the submission

Trials and associated reports presented in the submission
Trial ID	Protocol title/ Publication title	Publication citation
Bioequivalence studies
P147	Clinical Study Report Protocol 147 A definitive bioequivalence study for Janumet XR tablets in healthy subjects.	Internal Study Report
P300	Clinical Study Report Protocol 300 A relative bioavailability study with administration of single Janumet XR 500mg/50mg tablet and co-administration of Australian-sourced sitagliptin (JANUVIA) and metformin XR (Diabex XR) as individual tablets administered under fasting conditions and following consumption of a high-fat meal.	Internal Study Report
P317	Clinical Study Report Protocol 317 A relative bioavailability study with administration of single dose Janumet XR 1000mg/100mg tablet and co-administration of Australian-sourced sitagliptin (JANUVIA) and metformin XR (Diabex XR) as individual tablets administered under fasting conditions and following consumption of a high-fat meal.	Internal Study Report
Pharmacokinetics studies
P164	Clinical Study Report Protocol 164 A food-effect study for Janumet XR	Internal Study Report
P165	Clinical Study Report Protocol 165 A multiple-dose study to assess the pharmacokinetics of Janumet XR	Internal Study Report

8. Results of Trials

With regard to comparative effectiveness, the bioequivalence of the sitagliptin component of the FDC was supported by evidence from Study P147. This study also provided evidence for the bioequivalence of two metformin XR/sitagliptin FDC 500mg/50mg tablets with one 1000mg/100mg tablet. Although not included in the submission, Study P147 reported bioequivalence data for metformin which were presented in the commentary.

The bioequivalence of the metformin XR component of the FDC was supported by evidence from Studies P300 and P317. The clinical trial reports for P300 and P317 do not report bioequivalence data for sitagliptin.

The PBAC noted that the TGA had completed its evaluation of the bioequivalence data for the metformin XR/sitaglitpin FDC and that the FDC was approved for registration.

With regard to comparative harms, few serious adverse experiences were reported in the studies (P147, P300, P317), and additional pharmacokinetics studies included in the assessment of safety (P164, P165). The submission reported that nearly all the adverse experiences were mild and transient in nature, and consistent with the side effects of sitagliptin and metformin individual components. No patients died during the trials.

The submission presented data obtained from Periodic Safety Update Reports (PSUR) for sitagliptin, and for the metformin IR/sitagliptin FDC formulation. No new major safety issues were identified. After a review of post-marketing experiences for both sitagliptin and metformin IR/sitagliptin FDC, additional items were added to the adverse reactions list in the products’ PIs: arthralgia, myalgia, pain in extremity and back pain.

Patient relevant outcome study

The PBAC noted the advice from its Economics SubCommittee (ESC) that the only outcome data that had previously been presented for gliptins has been based on surrogate endpoints (in particular HbA1c), and agreed that patient relevant outcomes would be more informative.

The PBAC noted that a study is underway that will assess patient relevant outcomes with sitagliptin, ‘Trial Evaluating Cardiovascular Outcomes With Sitagliptin’. This trial is estimated to be complete in December 2014, and has the primary outcome of time to first confirmed cardiovascular event (for more information, please visit the ClinicalTrials.gov website). The PBAC requested it be provided with updates relating to the cardiovascular safety of sitagliptin as they become available.

In addition, the PBAC noted that an increase in the rate of pancreatitis, albeit non-significant, had been observed in clinical trials with alogliptin and saxagliptin. The PBAC considered this an important safety signal which requires ongoing monitoring and review, including for sitagliptin in case it is a class effect.

9. Clinical Claim

The submission described metformin XR/sitagliptin FDC 500mg/50mg, 1000mg/50mg and 1000mg/100mg as similar in efficacy and safety to the co-administration of the same doses of the individual components.

The PBAC considered this claim reasonable, but noted that a comparison with other metformin/gliptin FDCs was also appropriate and that no evidence was provided that this FDC is associated with an improvement in efficacy or a reduction in toxicity compared to other metformin/gliptin FDCs.

10. Economic Analysis

The submission presented a cost-minimisation analysis of metformin XR/sitagliptin FDC compared to metformin IR/sitagliptin FDC.

The equi-effective doses of metformin XR/sitagliptin FDC and metformin IR/sitagliptin FDC were estimated as:

Metformin XR/sitagliptin FDC 1000mg/100mg and 2 x metformin IR/sitagliptin FDC 500mg/50mg; and
Metformin XR/sitagliptin FDC 1000mg/50mg and metformin IR/sitagliptin FDC 1000mg/50mg.

For the reasons outlined below in the Recommendation and Reasons, the PBAC considered that the cost-effectiveness of the metformin XR/sitagliptin FDC would be acceptable if it were cost-minimised against the alogliptin/metformin FDC. The equi-effective doses of the gliptin component were considered to be 100 mg of sitagliptin and 25 mg of alogliptin. The PBAC agreed that ex-manufacturer price of the metformin XR component should be equivalent to the ex-manufacturer price of the corresponding amount of metformin IR in the metformin IR/sitagliptin FDC.

11. Estimated PBS Usage and Financial Implications

The submission estimated the likely number of prescriptions on the PBS with the listing of metformin XR/sitagliptin to be between 100,000 and 200,000 scripts in Year 5, and a total of greater than 500,000 scripts in the first 5 years of listing.

The PBAC recalled that in its April 2013 consideration of the DUSC Analysis of Medicines for Type 2 Diabetes, it had noted that the use of gliptin FDC products substantially exceeds the expected utilisation. The PBAC considered that the listing of the metformin/sitagliptin FDC as recommended would not be expected to increase the rate of growth of the metformin/gliptin FDCs but rather take a share of the existing metformin/gliptin FDC market. Thus, any financial impact would be limited and result from substitution of gliptin FDCs in packs containing 28 days of supply with those containing 30 days of supply and vice versa.

The PBAC considered that although there may be a small cost increase to the PBS involved in substitution of the metformin XR/sitagliptin FDC for the metformin IR/vildagliptin FDC due to the requirement for liver function testing with metformin IR/vildagliptin, this would not represent an additional cost to Government since the liver function test is subsidised through the MBS.

12. Recommendation and Reasons

The PBAC considered the sponsor’s submission, the Commentary and ESC advice for the submission and the sponsor’s responses to the Commentary and ESC advice.

The PBAC recommended the fixed dose combination metformin XR with sitagliptin for listing on the PBS for the treatment of Type 2 diabetes in a patient whose HbA1c is greater than 7% despite treatment with metformin. For the reasons outlined below, the PBAC considered that the cost-effectiveness of the metformin XR/sitagliptin FDC would be acceptable if it were cost-minimised against the alogliptin/metformin FDC. The equi-effective doses of the gliptin component were considered to be 100 mg of sitagliptin and 25 mg of alogliptin. The ex-manufacturer price of the metformin XR component should be equivalent to the ex-manufacturer price of the corresponding amount of metformin IR in the metformin IR/sitagliptin FDC.

In making this recommendation, the PBAC recalled its April 2013 consideration of the DUSC Analysis of Medicines for Type 2 Diabetes. At that time, the PBAC “noted that 46.7% of patients initiated on a regimen containing a gliptin+metformin FDC had been supplied only metformin as pre-initiation treatment. The PBAC considered whether it could estimate the likely true frequency of patients who are intolerant to sulfonylureas, or in whom the class of drugs is contraindicated. No precise estimates were identified in the review, and the product information documents for existing sulfonylureas include only general warning statements without quantification. The PBAC considered that ‘intolerance’ to sulfonylurea is being interpreted more liberally in practice than was anticipated. While noting prescriber concerns about risk of hypoglycaemia particularly in the elderly with some sulfonylureas the PBAC considered that the true rate of contraindication or intolerance would be very small, less than 5% of the patient population. The PBAC considered that the majority of the 46.7% were probably supplied gliptin+metformin FDCs under circumstances that were non-compliant with PBS criteria. Again, the PBAC noted that the cost-effectiveness of this treatment regimen (i.e. dual therapy as an alternative to sulfonylureas in a population WITHOUT contraindications) has not been established.”

The PBAC further recalled that it had recommended FDCs of metformin/linagliptin and metformin/saxagliptin at its April 2013 meeting and alogliptin at its July 2013 meeting. The listings of these two FDCs and alogliptin were recommended at a lower price and with a different restriction than the currently subsidised gliptin FDCs or single agents to take into account the likely proportion of non-cost-effective use of the gliptins as identified by the DUSC review.

The PBAC also noted that the Department’s advice at the meeting that the Minister (through his Delegate) intends to declare alogliptin as a pharmaceutical benefit under section 85(2) of the National Health Act 1953 (the Act) and that the PBS listing will proceed with a price and restriction consistent with the PBAC recommendation of July 2013.

The PBAC acknowledged the sponsor’s responses to the PES Commentary and ESC advice, in particular the sponsor’s assertions that the following issues must be taken into account by PBAC:

in patient groups where cost-effectiveness has not been established, the value should be based on more than HbA1c, and
the proportion of use where cost-effectiveness has not been established is considerably smaller than proposed in the DUSC report and public summary documents for linagliptin/metformin and saxagliptin/metformin FDCs and is around 15%.

The PBAC further noted that the sponsor had, in its initial March 2008 submission to PBAC, claimed that treatment with sitagliptin is cost-effective over sulfonylureas, but that PBAC had rejected that claim because of “uncertain evidence of a clinically relevant benefit over the comparator, sulfonylureas, and because of the resulting highly uncertain cost-effectiveness” [PSD, 2008 sitagliptin, available on the PBS website].

Notwithstanding the issues raised by the sponsor, because the PBAC considers sitagliptin offers no improvement in efficacy or reduction in toxicity over alogliptin, the PBAC considered it is appropriate for the subsidy price for the sitagliptin component of the FDC, to be cost minimised against alogliptin.

With respect to the price of the metformin component of the FDC, the PBAC considered that the approach proposed in the sponsor’s submission for the metformin XR/sitagliptin FDC is appropriate in the absence of any evidence that this FDC is associated with an improvement in efficacy or a reduction in toxicity compared to other gliptin/metformin FDCs.

The PBAC considered that a listing with removal of the requirement for patients to be contraindicated or intolerant of sulfonylureas was appropriate for this FDC, and noted that an amended listing of the same type for the sitagliptin with metformin IR FDC, the simvastatin with sitagliptin FDC and for single ingredient sitagliptin benefits would also be appropriate should a new lower price be agreed.

The PBAC considered the proliferation of metformin/gliptin FDCs and range of doses of both the gliptin and metformin components available creates the potential for prescriber and patient confusion. Of particular concern is the 1000mg/100mg strength of the metformin XR/sitagliptin FDC which PBAC considered has increased potential for dose confusion, as the standard dose for metformin is 2000mg per day (= 2 tablets) and the standard dose for sitagliptin is 100 mg per day (= 1 tablet).

The Safety Net 20 Day Rule should apply.

The PBAC reconfirmed its earlier recommendation that the metformin/sitagliptin FDC is suitable for inclusion in the list of PBS medicines for prescribing by nurse practitioners within collaborative arrangements.

The PBAC advised the Minister that under Section 101(3BA) of the Act, sitagliptin with metformin fixed dose combination should be treated as interchangeable on an individual patient basis with:

i) alogliptin with metformin fixed dose combination; and

ii) linagliptin with metformin fixed dose combination; and

iii) vildagliptin with metformin fixed dose combination; and

iv) saxagliptin with metformin fixed dose combination.

Outcome:

Recommended

Metformin with Sitagliptin listing
Name, Restriction, Manner of administration and form	Max. Qty	No. of Rpts	Proprietary Name and Manufacturer
Metformin hydrochloride extended release/sitagliptin Tablet, 1000mg/50mg	56	5	Janumet^® XR	Merck Sharp & Dohme
Metformin hydrochloride extended release/sitagliptin Tablet, 1000mg/100mg	28	5	Janumet^® XR	Merck Sharp & Dohme

Metformin with Sitagliptin restriction
Condition/Indication:	Diabetes mellitus type 2
Restriction:	Authority required (STREAMLINED)
Clinical criteria:	Patient must have, or have had, a HbA1c measurement greater than 7% despite treatment with metformin; OR Patient must have, or have had, where HbA1c measurement is clinically inappropriate, blood glucose levels greater than 10 mmol per L in more than 20% of tests over a 2 week period despite treatment with metformin.
Prescriber Instructions	The date and level of the qualifying HbA1c measurement must be, or must have been, documented in the patient's medical records at the time treatment with a gliptin, a glitazone, a glucagon-like peptide-1 or an SGLT2 inhibitor is initiated. The HbA1c must be no more than 4 months old at the time treatment with a gliptin, a glitazone, a glucagon-like peptide-1 or an SGLT2 inhibitor was initiated. Blood glucose monitoring may be used as an alternative assessment to HbA1c levels in the following circumstances: (a) A clinical condition with reduced red blood cell survival, including haemolytic anaemias and haemoglobinopathies; and/or (b) Had 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 glucagon-like peptide-1 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.
Administrative Advice	This fixed dose combination is not PBS-subsidised for use in combination with a sulfonylurea (triple oral therapy), as initial therapy or in combination with a thiazolidinedione (glitazone), a glucagon-like peptide-1 or an SGLT2 inhibitor.

Metformin with Sitagliptin restriction
Condition/Indication:	Diabetes mellitus type 2
Treatment Phase	Continuing
Restriction:	Authority required (STREAMLINED)
Clinical criteria:	Patient must have previously received and been stabilised on a PBS-subsidised regimen of oral diabetic medicines which includes metformin and sitagliptin.
Administrative Advice	This fixed dose combination is not PBS-subsidised for use in combination with a sulfonylurea (triple oral therapy), as initial therapy or in combination with a thiazolidinedione (glitazone), a glucagon-like peptide-1 or an SGLT2 inhibitor.

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 comment.