Insulin glargine 300 IU/mL solution (Toujeo) for diabetes mellitus

• Long-acting insulin for adults with type 1 and 2 diabetes
  Insulin glargine 300 IU/mL solution (Gla-300) is a basal insulin, administered subcutaneously once daily. It is approved only for use in patients aged ≥ 18 years.
• Similar efficacy and safety to that of insulin glargine 100 IU/mL solution (Gla-100)
  Gla-300 is a concentrated formulation of the already PBS-listed Gla-100. Over 6 months Gla-300 provided similar glycaemic control and had comparable rates of adverse events to those for Gla-100.
• Similar to, but not interchangeable with, Gla-100
  Dose adjustments and close monitoring are required when switching from one formulation to the other.

Unrestricted benefits

Gla-300 has an Unrestricted benefits listing on the Pharmaceutical Benefits Scheme (PBS);^1,2 however, it is approved by the Therapeutic Goods Administration (TGA) for the treatment of diabetes mellitus in adults only.^3,4

May be prescribed by nurse practitioners

Authorised nurse practitioners may prescribe this medicine on the PBS. 

See the PBS website for more information on nurse practitioner PBS prescribing

Gla-300 is a long-acting human insulin analogue administered subcutaneously, once daily.^5,6 It is packaged in a disposable prefilled injector pen containing 450 IU of insulin glargine in 1.5 mL of solution.⁵

Gla-300 is a concentrated formulation of the already PBS-subsidised Gla-100. According to a pharmacokinetics and pharmacodynamics study, Gla-300 has a slightly different activity profile to that of Gla-100, which may result in a more constant glucose-lowering effect over 24 hours.⁷

Gla-300 is an alternative basal insulin for adults with type 1 or type 2 diabetes requiring long-acting insulin.

Convenient for patients requiring high-dose insulin

The increased number of units of insulin per injection pen may be convenient for patients who require a large dose of insulin, as a single pen contains more doses.

The increased number of units of insulin, coupled with the same shelf life for opened products as other insulins (28 days), may result in wastage in a small group of patients taking less than 16 units daily.

For use by patients aged ≥ 18 years

Gla-300 is TGA-approved for use by patients aged ≥ 18 years only; safety and efficacy have not been established in patients under 18 years.³

Gla-300 joins Gla-100 and detemir on the list of long-acting basal insulins currently available in Australia. Unlike the insulin glargine formulations that have an Unrestricted benefits listing on the PBS, detemir is only available on the PBS for patients with type 1 diabetes.^8,9

Type 1 diabetes: first-line therapy

An insulin regimen consisting of basal insulin plus mealtime bolus insulin is recommended as a first-line treatment for patients with type 1 diabetes.¹⁰ A long-acting basal insulin (glargine or detemir) is preferred to intermediate-acting insulin (isophane) for the basal component, and a very-short-acting insulin is preferred for the bolus component of treatment.¹⁰

Type 2 diabetes: second-line therapy

Patients not meeting glycaemic targets with metformin should have a second diabetes medicine added to their therapy.

Basal insulin is one option for second-line add-on therapy; other options include a sulfonylurea, dipeptidyl-peptidase-4 inhibitor (gliptin), sodium glucose co-transporter 2 (SGLT2) inhibitor, glucagon-like-peptide-1 agonist, thiazolidinedione (glitazone) or acarbose.^10-12

National RACGP guidelines on the management of type 2 diabetes in general practice include recommendations about adding on second-line therapy.

The safety and efficacy of Gla-300 was compared with that of Gla-100 only. There are no data on the comparative efficacy of Gla-300 and other diabetes medicines.

A number of Phase 3 head-to-head clinical trials have been published comparing Gla-300 with Gla-100 in patients with type 1 diabetes^13,14 and in patients with type 2 diabetes.^15-18 Trials included an initial 6-month treatment period followed by a 6-month extension period.

Patients in all trials were aged 18 years or over, with a baseline HbA_1c (glycated haemoglobin) of 53–86 mmol/mol (7–10%) for those with type 1 diabetes, and 53–97 mmol/mol (7–11%) for those with type 2 diabetes.^13-18

In all trials, basal insulin was administered once daily.

The dose was generally titrated once weekly and no more than every 3 to 4 days, aiming for a fasting self-monitored plasma glucose target of 4.4–7.2 mmol/L in the type 1 diabetes trials^13,14 and 4.4–5.6 mmol/L in the type 2 diabetes trials.^15-18 Cessation of titration was left to the individual judgement of the investigators and participants.¹⁵

All trials were open label because the two glargine solutions were administered using different injection devices. The potential for biased safety and efficacy outcomes due to lack of blinding cannot be excluded.

Similar efficacy to that of Gla-100 for glycaemic control

Over 12 months Gla-300 provided comparable blood glucose control to that of Gla-100 for people with type 1 diabetes, as measured by HbA_1c levels:¹⁴

• mean reduction in HbA_1c was 0.20% (2.2 mmol/mol) for Gla-300 and 0.22% (2.4 mmol/mol) for
  Gla-100.
  

Patient-level meta-analysis of the pivotal Phase 3 trials for people with type 2 diabetes showed that treatment with Gla-300 or Gla-100 over 12 months was associated with:

• a mean reduction in HbA_1c from baseline of 0.91% (–9.95 mmol/mol) for Gla-300 and 0.80 % (–8.74 mmol/mol) for Gla-100^{18,19 20,21}
  
• a least squares mean between-group difference (95% CI) from baseline of –0.10 (–0.18 to –0.02)% or −1.09 mmol/mol (95% CI −2.01 to −0.20); p = 0.0174 (Gla-300, n = 1165; Gla-100, n = 1170).
  

At 12-month follow-up, a slightly higher dose of Gla-300, compared with Gla-100, was needed to maintain similar control of blood sugar levels:

• type 1 diabetes: 15.6% higher dose^13,14
  
• type 2 diabetes: 14% higher dose.^18,19
  

The cause of the higher dose requirement might be due to a slight decrease in the bioavailability of Gla-300.^15,19 It is speculated that Gla-300 resides in the subcutaneous space longer than Gla-100, which leads to a larger amount of the insulin being inactivated by tissue peptidases at the injection site.^15,19

Slight differences in weight gain

Over the initial 6-month trial period, patients with type 1 diabetes who received Gla-300 generally gained slightly less weight (mean increase of 0.5 kg) than those who received Gla-100 (mean increase of 1.0 kg).^13,19 This statistically significant difference was lost at 12 months.¹⁴

During the 12-month trial period, for people with type 2 diabetes treated with Gla-300, significantly less weight gain was observed compared with those treated with Gla-100 (mean between-group difference –0.40 kg, 95% CI –0.71 to –0.09, p = 0.01).¹⁸

The glargine molecule in both the 300 IU and 100 IU formulations is the same, so, as might be anticipated, types and rates of adverse events were similar for both treatment groups.

For information about reporting adverse reactions to the TGA, or to report suspected adverse reactions online, see the TGA website.

Hypoglycaemia

Rates of hypoglycaemic events with Gla-300 and Gla-100 over the initial 6-month trial period were as follows.

• A similar proportion of patients with type 1 diabetes reported one or more confirmed (≤ 3.9 mmol/L) or severe hypoglycaemic events in both treatment groups; 93% in the Gla-300 group and 94% in the Gla-100 group.¹³
  
• For patients with type 2 diabetes, pooled analysis reported a lower cumulative number of confirmed or severe hypoglycaemic events per participant with Gla-300 compared with Gla-100 at any time of the day. Similar trends were observed when rates were annualised for any time of the day and for nocturnal events only.
  

For people with type 1 diabetes treated over 12 months, confirmed or severe hypoglycaemic events were similar across both groups, with most participants experiencing one or more nocturnal events (73%, Gla-300; 75%, Gla-100).¹⁴

For people with type 2 diabetes treated over 12 months, annualised rates of confirmed or severe hypoglycaemia were comparable between groups for any time of the day (rate ratio 0.97, 95% CI 0.87 to 1.09), but lower for Gla-300 when nocturnal events only were considered (rate ratio 0.82, 95% CI 0.67 to 0.99).¹⁸

Severe hypoglycaemic events were defined as those needing assistance by another person to administer therapy.¹⁵

• In the 6-month trial period fewer patients reported severe hypoglycaemia with Gla-300 (6.6%) than with Gla-100 (9.5%).¹³
  
• Similar findings were reported in the 12-month trial period, where 9% of patients treated with Gla-300 and 11% of patients with Gla-100 reported severe hypoglycaemia.¹⁴
  

Other adverse events

Rates of treatment-emergent adverse events (TEAEs) were similar for Gla-300 and Gla-100 for patients with either type 1 or type 2 diabetes.^13,14,18,19

Other than hypoglycaemia, injection-site reactions were the most frequently reported TEAEs considered related to the study treatment.^16,18

• For patients with type 2 diabetes, 3% in the Gla-300 group and 3.5% in the Gla-100 group experienced injection site reactions.^18,19
  
• For patients with type 1 diabetes, the corresponding figures were 2.2% in the Gla-300 group and 1.5% in the Gla-100 group in the 6-month trial period.¹³ In the 12-month period, 2.9% of participants in the Gla-300 group and 1.5% of participants in the Gla-100 group experienced injection site reactions.¹⁴
  

The Pharmaceutical Benefits Advisory Committee (PBAC) recommended the listing of Gla-300 for the treatment of diabetes mellitus on the basis of cost-minimisation compared with Gla-100.²²

The PBAC accepted that Gla-300 is non-inferior in effectiveness to Gla-100 but did not accept that it improved the incidence of hypoglycaemic events on a population basis.¹

Gla-300 is a subcutaneous injection administered once daily. Each Gla-300 prefilled pen injector contains 450 IU of insulin glargine. The dose to be injected can be adjusted in increments of 1 IU and is shown in the dose counter of the pen. A dose of 1–80 IU can be given in a single injection.⁵

Unlike Gla-100, Gla-300 is not currently available in a vial.

Recommended initial dosages for Gla-300 are shown below. As with other insulins, subsequent dose adjustment is determined on an individual basis according to patient characteristics and goals of therapy.^5,22

Starting insulin

Insulin dosage needs to be individualised for patients starting insulin therapy – consult guidelines.^11,22 In type I diabetes mellitus, Gla-300 must be combined with short/rapid-acting insulin in order to cover mealtime insulin requirements. In type 2 diabetes, the recommended daily starting dose is 0.2 IU/kg body weight followed by individual dosage adjustments. Also, for patients with type 2 diabetes mellitus, Gla-300 can be given together with orally active antidiabetic medicinal products.⁵

Switching between Gla-300 and Gla-100

• Gla-300 and Gla-100 are not directly interchangeable.
  
• When switching from Gla-100 to Gla-300, start with a unit-for-unit dose switch; however, a higher dose of Gla-300 may be required to achieve treatment targets.⁵
  
• When switching from Gla-300 to Gla-100, start with a reduced dose. The starting dose of Gla-100 should be about 20% less than the dose of the Gla-300 being discontinued.⁵
  

Switching from other basal insulin

• From a once-daily insulin: start with a unit-for-unit dose of the basal insulin being discontinued.⁵
  
• From a twice-daily basal insulin: start with 80% of the total daily dose of the basal insulin being discontinued.⁵
  

When changing from one basal insulin to another, the dosage of short-acting or very short-acting insulin and oral diabetes medicines may also need to be adjusted.¹⁰

Close monitoring of blood glucose is also recommended during the change and in the following weeks.¹⁰

Special populations

Gla-300 can be used by older patients (aged ≥ 65 years) but, as with any insulin, should be dosed conservatively to avoid hypoglycaemic events.⁵

There are no data on the use of Gla-300 during pregnancy or lactation.⁵ Exercise similar caution when prescribing Gla-300 as with other long-acting insulin formulations for these women.

Avoiding medicine errors

The prefilled pen device for both Gla-300 and Gla-100 is called ‘SoloStar’. To help distinguish between the two glargine products, Gla-300 is branded differently from Gla-100 and the ‘U300’ is highlighted in yellow on the label.⁵

Patients must exercise all usual precautions associated with use of an insulin pen, such as checking the label, visually verifying the number of selected units on the dose counter of the pen and not reusing needles.⁵

Administration

Gla-300 is administered once daily by subcutaneous injection in the abdominal, deltoid or thigh region.⁵

If more than 80 units of insulin are required to deliver a single dose of Gla-300, the split injections should be given at the same time.

Preferably Gla-300 should be administered at the same time each day, but if necessary it can be injected up to 3 hours before or after the usual time of administration.⁵

Inform the patient and/or carers that Gla-300:⁵

• is a long-acting insulin that controls blood glucose levels between meals for 24 hours
  
• is administered subcutaneously once daily
  
• is not interchangeable with any other basal insulin, including Gla-100, without individualised dose adjustment; blood glucose should be monitored closely during the switch and in the following weeks
  
• must not be used together with any other basal insulin
  
• is a clear solution and should not be confused with short-acting or very short-acting insulins, which are also clear solutions
  
• must not be diluted or mixed with any other insulin
• should only be administered using the prefilled pen device in which it is provided for use.
  

Ensure that the patient and/or carers are aware of the warning signs of hypoglycaemia and advise on factors that increase the risk of hypoglycaemia with insulins.

Discuss the Toujeo consumer medicine information (CMI) leaflet with the patient.