Figure 2: Mean GIR profile for 0.4 U/kg dose of TRESIBA (steady state) in patients with Type 1 diabetes mellitus

The mean maximum glucose lowering effect (GIRmax) of a 0.4 U/kg dose of TRESIBA was 2.0 mg/kg/min, which was observed at a median of 12 hours post-dose. The glucose lowering effect of TRESIBA lasted at least 42 hours after the last of 8 once-daily injections.

In patients with type 1 diabetes mellitus, the steady-state, within subjects, day-to-day variability in total glucose lowering effect was 20% with TRESIBA (within-subject coefficient of variation for AUCGIR,τ,SS).

The total glucose-lowering effect of TRESIBA over 24 hours measured in a euglycemic clamp study after 8 days of once-daily administration in patients with type 1 diabetes increases approximately in proportion to the dose for doses between 0.4 U/kg to 0.8 U/kg.

The total glucose-lowering effect of 0.4 U/kg of TRESIBA U-100 and 0.4 U/kg of TRESIBA U-200, administered at the same dose, and assessed over 24 hours in a euglycemic clamp study after 8 days of once-daily injection was comparable.

12.3 PharmacokineticsAbsorption

In patients with type 1 diabetes, after 8 days of once daily subcutaneous dosing with 0.4 U/kg of TRESIBA,maximum degludec concentrations of 4472 pmol/L were attained at a median of 9 hours (tmax). After the first dose of TRESIBA, median onset of appearance was around one hour.

Total insulin degludec concentration (i.e., exposure) increased in a dose proportional manner after subcutaneous administration of 0.4 U/kg to 0.8 U/kg TRESIBA. Total and maximum insulin degludec exposure at steady state are comparable between TRESIBA U-100 and TRESIBA U-200 when each is administered at the same U/kg dose.

Insulin degludec concentration reach steady state levels after 3-4 days of TRESIBA administration [see Dosage and Administration (2.2)].

Distribution

The affinity of insulin degludec to serum albumin corresponds to a plasma protein binding of >99% in human plasma. The results of the in vitro protein binding studies demonstrate that there is no clinically relevant interaction between insulin degludec and other protein bound drugs.

Elimination

The half-life after subcutaneous administration is determined primarily by the rate of absorption from the subcutaneous tissue. On average, the half-life at steady state is approximately 25 hours independent of dose. Degradation of TRESIBA is similar to that of insulin human; all metabolites formed are inactive. The mean apparent clearance of insulin degludec is 0.03 L/kg (2.1 L/h in 70 kg individual) after single subcutaneous dose of 0.4 U/kg.

Specific Populations

As with other insulin preparations, TRESIBA should always be titrated according to individual requirements.

Geriatrics-

Pharmacokinetic and pharmacodynamic response of TRESIBA in 13 younger adult (18−35 years) and 14 geriatric (≥65 years) subjects with type 1 diabetes following two 6 day periods of once-daily subcutaneous dosing with 0.4 U/kg dose of TRESIBA or insulin glargine. On average, the pharmacokinetic and pharmacodynamic properties of TRESIBA at steady-state were similar in younger adult and geriatric subjects, albeit with greater between subject variability among the geriatric subjects.

Gender-

The effect of gender on the pharmacokinetics of TRESIBA w