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Novolog Mix 70-30

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NovoLog Mix 70/30

NovoLog Mix 70/30

CLINICAL PHARMACOLOGY

Mechanism of Action

The primary activity of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) is the regulation of glucose metabolism. Insulins, including NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) , bind to the insulin receptors on muscle, liver and fat cells and lower blood glucose by facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose from the liver.

Pharmacodynamics

The two euglycemic clamp studies described below assessed glucose utilization after dosing of healthy volunteers. NovoLog Mix 70/30 has an earlier onset of action than human premix 70/30 in studies of normal volunteers and patients with diabetes. The onset of action is between 10-20 minutes for NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) compared to 30 minutes for Novolin 70/30. The mean ± SD time to peak activity for NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) is 2.4 hr ± 0.8hr compared to 4.2 hr ± 0.4 hr for Novolin 70/30. The duration of action may be as long as 24 hours (see Figure 2).

Figure 2: Pharmacodynamic Activity Profile of NovoLog Mix 70/30 and Novolin 70/30 in healthy subjects.

Pharmacodynamic Activity Profile - Illustration

Pharmacokinetics

The single substitution of the amino acid proline with aspartic acid at position B28 in insulin aspart (NovoLog) reduces the molecule'stendency to form hexamers as observed with regular human insulin. The rapid absorption characteristics of NovoLog are maintained by NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) . The insulin aspart in the soluble component of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) is absorbed more rapidly from the subcutaneous layer than regular human insulin. The remaining 70% is in crystalline form as insulin aspart protamine which has a prolonged absorption profile after subcutaneous injection.

Bioavailability and Absorption

The relative bioavailability of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) compared to NovoLog and Novolin 70/30 indicates that the insulins are absorbed to similar extent. In euglycemic clamp studies in healthy volunteers (n=23) after dosing with NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) (0.2 U/kg), a mean maximum serum concentration (Cmax) of 23.4 ± 5.3 mU/L was reached after 60 minutes. The mean half-life (t½) of NovoLog Mix 70/30 was about 8 to 9 hours. Serum insulin levels returned to baseline 15 to 18 hours after a subcutaneous dose of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) . Similar data were seen in a separate euglycemic clamp study in healthy volunteers (n=24) after dosing with NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) (0.3 U/kg). A Cmax of 61.3 ± 20.1 mU/L was reached after 85 minutes. Serum insulin levels returned to baseline 12 hours after a subcutaneous dose.

The Cmax and the area under the insulin concentration-time curve (AUC) after administration of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) was approximately 20% greater than those after administration of Novolin 70/30, (see Fig. 3 for pharmacokinetic profiles).

Figure 3: Pharmacokinetic Profiles of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) and Novolin 70/30

Pharmacokinetic Profiles - Illustration

Distribution and Elimination

NovoLog has a low binding to plasma proteins, 0 to 9%, similar to regular human insulin. After subcutaneous administration in normal male volunteers (n=24), NovoLog was more rapidly eliminated than regular human insulin with an average apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.

The effect of sex, age, obesity, ethnic origin, renal and hepatic impairment, pregnancy, or smoking, on the pharmacodynamics and pharmacokinetics of NovoLog Mix 70/30 has not been studied.

Animal Toxicology and/or Pharmacology

In standard biological assays in mice and rabbits, one unit of NovoLog has the same glucose-lowering effect as one unit of regular human insulin. However, the effect of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) is more rapid in onset compared to Novolin (human insulin) 70/30 due to its faster absorption after subcutaneous injection.

Clinical Studies

NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) versus Novolin 70/30

In a three-month, open-label trial, patients with Type 1 (n=104) or Type 2 (n=187) diabetes were treated twice daily (before breakfast and before supper) with NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) or Novolin 70/30. Patients had received insulin for at least 24 months before the study. Oral hypoglycemic agents were not allowed within 1 month prior to the study or during the study. The small changes in HbA1c were comparable across the treatment groups (see Table 3).

Table 3: Glycemic Parameters at the End of Treatment [Mean ± SD (N subjects)]

  NovoLog Mix 70/30 Novolin 70/30
Type 1, N=104
  Fasting Blood Glucose (mg/dL) 174 ± 64 (48) 142 ± 59 (44)
  1.5 Hour Post Breakfast (mg/dL) 187 ± 82 (48) 200 ± 82 (42)
  1.5 Hour Post Dinner (mg/dL) 162 ± 77 (47) 171 ± 66 (41)
  HbA1c (%) Baseline 8.4 ± 1.2 (51) 8.5 ± 1.1 (46)
  HbA1c (%) Week 12 8.4 ± 1.1 (51) 8.3 ± 1.0 (47)
Type 2, N=187
  Fasting Blood Glucose (mg/dL) 153 ± 40 (76) 152 ± 69 (93)
  1.5 Hour Post Breakfast (mg/dL) 182 ± 65 (75) 200 ± 80 (92)
  1.5 Hour Post Dinner (mg/dL) 168 ± 51 (75) 191 ± 65 (93)
  HbA1c (%) Baseline 8.1 ± 1.2 (82) 8.2 ± 1.3 (98)
  HbA1c (%) Week 12 7.9 ± 1.0 (81) 8.1 ± 1.1 (96)

The significance, with respect to the long-term clinical sequelae of diabetes, of the differences in postprandial hyperglycemia between treatment groups has not been established.

Specific anti-insulin antibodies as well as cross-reacting anti-insulin antibodies were monitored in the 3-month, open-label comparator trial as well as in a long-term extension trial

Combination Therapy: Insulin and Oral Agents in Patients with Type 2 Diabetes

Trial 1:

In a 34-week, open-label trial, insulin-na´ve patients with type 2 diabetes currently treated with 2 oral antidiabetic agents were switched to treatment with metformin and pioglitazone. During an 8-week optimization period metformin and pioglitazone were increased to 2500 mg per day and 30 or 45 mg per day, respectively. After the optimization period, subjects were randomized to receive either NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) twice daily added on to the metformin and pioglitazone regimen or continue the current optimized metformin and pioglitazone therapy. NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) was started at a dose of 6 IU twice daily (before breakfast and before supper). Insulin doses were titrated to a pre-meal glucose goal of 80-110 mg/dL. The total daily insulin dose at the end of the study was 56.9 ± 30.5 IU.

Table 4: Combination Therapy with Oral Agents and Insulin in Patients with Type 2 Diabetes Mellitus [Mean (SD)]

Treatment duration 24-weeks NovoLog Mix 70/30 + Metformin +
Pioglitazone
Metformin + Pioglitazone
HbA1c
  Baseline mean ± SD (n) 8.1 ±1.0 (102) 8.1 ±1.0 (98)
  End-of-study mean ±SD (n) - LOCF 6.6 ± 1.0 (93) 7.8 ±1.2 (87)
  Adjusted Mean change from baseline ±SE (n)* -1.6 ±0.1 (93) -0.3 ±0.1 (87)
  Treatment difference mean ±SE* -1.3 ±0.1
  95% CI* (-1.6, -1.0)
Percentage of subjects reaching HbA1c < 7.0% 76% 24%
Percentage of subjects reaching HbA1 < ≤ 6.5% 59% 12%
Fasting Blood Glucose (mg/dL)
  Baseline Mean ± SD (n) 173 ±39.8 (93) 163 ±35.4 (88)
  End of Study Mean ± SD (n) – LOCF 130 ±50.0 (90) 162 ±40.8 (84)
  Adjusted Mean change from baseline ±SE (n)* -43.0 ±5.3 (90) -3.9 ±5.3 (84)
End-of-Study Blood Glucose (Plasma) (mg/dL)
  2 Hour Post Breakfast 138 ±42.8 (86) 188 ± 57.7 (74)
  2 Hour Post Lunch 150 ±41.5 (86) 176 ±56.5 (74)
  2 Hour Post Dinner 141 ±57.8 (86) 195 ±60.1 (74)
% of patients with severe hypoglycemia** 3 0
% of patients with minor hypoglycemia** 52 3
Weight gain at end of study (kg)** 4.6 ±4.3 (92) 0.8 ±3.2 (86)
*Adjusted mean per group, treatment difference, and 95% CI were obtained based on an ANCOVA model with treatment, FPG stratum, and secretagogue stratum as fixed factors and baseline HbA1c as the covariate.
**If metabolic control is improved by intensified insulin therapy, an increased risk of hypoglycemia and weight gain may occur.

Trial 2:

In a 28-week, open-label trial, insulin-na´ve patients with type 2 diabetes with fasting plasma glucose above 140 mg/dL currently treated with metformin ± thiazolidinedione therapy were randomized to receive either NovoLog Mix 70/30 twice daily [before breakfast and before supper] or insulin glargine once daily1 (see Table 5). NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) was started at an average dose of 5-6 IU (0.07 ± 0.03 IU/kg) twice daily (before breakfast and before supper), and bedtime insulin glargine was started at 10-12 IU (0.13 ± 0.03 IU/kg). Insulin doses were titrated weekly by decrements or increments of -2 to +6 units per injection to a pre-meal glucose goal of 80-110 mg/dL. The metformin dose was adjusted to 2550 mg/day. Approximately one-third of the patients in each group were also treated with pioglitazone (30 mg/day). Insulin secretagogues were discontinued in order to reduce the risk of hypoglycemia. Most patients were Caucasian (53%), and the mean initial weight was 90 kg.

Table 5: Combination Therapy with Oral Agents and Two Types of Insulin in Patients with Type 2 Diabetes Mellitus [Mean (SD)]

Treatment duration 28-weeks NovoLog Mix 70/30 + Metformin ± Pioglitazone Insulin Glargine +Metformin ± Pioglitazone
  Number of patients 117 116
HbA1c
  Baseline mean (%) 9.7 ±1.5 (117) 9.8 ± 1.4 (114)
  End-of-study mean 6.9 ±1.2 (108) 7.4 ±1.2 (114)
  Mean change from baseline -2.7 ±1.6 (108) -2.4 ±1.5 (114)
Percentage of subjects reaching HbA1c < 7.0% 66% 40%
Total Daily Insulin Dose at end of study (U) 78 ±40 (117) 51 ±27 (116)
% of patients with severe hypoglycemia 0 0
% of minor hypoglycemia 43 16
Weight gain at end of study 5.4 ±4.8 (117) 3.5 ±4.5 (116)

REFERENCES

1. Raskin R, Allen E, Hollander P, et al. Initiating insulin therapy in type 2 diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care. 2005; 28:260-265.

Last reviewed on RxList: 6/9/2010
This monograph has been modified to include the generic and brand name in many instances.

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