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Novolog Mix 50-50

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NovoLog Mix 50/50

CLINICAL PHARMACOLOGY

Mechanism of action

The primary activity of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) is the regulation of glucose metabolism. Insulin products including the insulin in NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) , exert their specific action through binding to insulin receptors.

Insulin binding activates mechanisms to lower blood glucose by facilitating cellular uptake of glucose into skeletal muscle and fat while simultaneously inhibiting the output of glucose from the liver.

In standard biological assays in mice and rabbits, one unit of NovoLog® (insulin aspart) has the same glucose-lowering effect as one unit of regular human insulin.

Pharmacokinetics

Bioavailability and Absorption

The single substitution of the amino acid proline with aspartic acid at position B28 in insulin aspart (NovoLog®) reduces the molecule's rm hexamers as observed with regular human insulin. This results in more rapid absorption from the subcutaneous spaces than seen with regular human insulin. The rapid absorption characteristics of NovoLog® are maintained by NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) , containing 50% insulin aspart in soluble form. The remaining 50% is in crystalline form as insulin aspart protamine which has a prolonged absorption profile after subcutaneous injection.

In an euglycemic clamp study in patients with type 1 diabetes (n=32) after dosing with 0.4 U/kg of NovoLog® Mix 70/30, 50/50, and NovoLog® on three different study days, a Cmax of 98 mU/L was reached after approximately 80 minutes for NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) (See Table 1). There was diminishing distinction in pharmacokinetics between the two NovoLog Mix formulations at later time points (See Figure 2).

Table 1: Pharmacokinetic Parameters comparing NovoLog® Mix 50/50 to NovoLog® Mix 70/30 and NovoLog® in patients with Type 1 diabetes mellitus

  NovoLog® Mix 50/50 versus NovoLog® Mix 70/30 NovoLog® versus
NovoLog® Mix 50/50
Cmax 1.49 [1.34; 1.65] 2.04 [1.84; 2.26]
AUC0-2h 1.48 [1.35; 1.64] 2.01 [1.82; 2.22]

Values are expressed as mean ratios [95% confidence intervals]

Figure 2. Pharmacokinetic profiles of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) , 70/30, and NovoLog® in Patients with Type 1 diabetes mellitus

Pharmacokinetic profiles of NovoLog® Mix 50/50, 70/30, and NovoLog® in Patients with Type 1 diabetes mellitus  - Illustration

The bioavailability of insulin aspart is decreased with increasing protamine sulfate concentration in any NovoLog® Mix formulation. Consequently, exposure of a subcutaneous dose of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) may be reduced in comparison to the comparable dose of insulin aspart (NovoLog® ) and an intermediate insulin that are mixed by the patient prior to injection. No clinical studies have been conducted comparing NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) to proportionate doses of insulin aspart (NovoLog® ) and an intermediate-acting insulin that are mixed by the patient prior to injection. Switching to a regimen that contains a NovoLog® Mix formulation will require careful blood glucose monitoring to ensure adequacy of glycemic control and to avoid hypoglycemia.

The rate of insulin absorption and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables (see PRECAUTIONS, General). The influence of different injection sites on the absorption of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) has not been investigated.

Distribution and Elimination

NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) is a biphasic insulin which contains 50% soluble insulin aspart. NovoLog® has a low binding to plasma proteins, 0 - 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.

Pharmacodynamics

In an euglycemic clamp study in subjects with type 1 diabetes, a maximum glucose infusion rate (GIRmax) of 6.0 ± 1.7 ter approximately 2.5 hours for NovoLog® Mixmg/kg/min was 50/50 (See Table 2). There was diminishing distinction in pharmacodynamics between the two NovoLog Mix formulations at later time points (See Figure 3).

Table 2: Pharmacodynamic Parameters comparing NovoLog® Mix 50/50 to NovoLog® Mix 70/30 and NovoLog®in patients with Type 1 diabetes mellitus

  NovoLog® Mix 50/50 versus
NovoLog® Mix 70/30
NovoLog® versus
NovoLog® Mix 50/50
GIRmax 1.29 [1.17; 1.43] 1.49 [1.35; 1.65]
AUCGIR,0-2h 1.52 [1.31; 1.78] 1.44 [1.23; 1.67]

Values are expressed as mean ratios [95% confidence intervals]

Figure 3. Pharmacodynamic profiles of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) , 70/30, and NovoLog® in patients with Type 1 diabetes mellitus

Pharmacodynamic profiles of NovoLog® Mix 50/50, 70/30, and NovoLog® in patients with Type 1 diabetes mellitus  - Illustration

Special populations

Children and adolescents - The pharmacokinetic and pharmacodynamic properties of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) have not been assessed in children and adolescents less than 18 years of age.

Geriatrics - The effect of age on the pharmacokinetics and pharmacodynamics of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) has not been studied.

Gender - The effect of gender on the pharmacokinetics and pharmacodynamics of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) has not been studied.

Obesity - The effect of obesity and/or subcutaneous fat thickness on the pharmacokinetics and pharmacodynamics of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) has not been studied but data on the rapid-acting component (NovoLog®) show no significant effect.

Ethnic origin - The effect of ethnic origin on the pharmacokinetics and pharmacodynamics of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) has not been studied

Renal impairment - The effect of renal function on the pharmacokinetics and pharmacodynamics of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) has not been studied but data on the rapid-acting component (NovoLog®) show no significant effect. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. Careful glucose monitoring and dose adjustments of insulin, including NovoLog® Mix 50/50 may be necessary in patients with renal dysfunction (see PRECAUTIONS, Renal Impairment).

Hepatic impairment - The effect of hepatic impairment on the pharmacokinetics and pharmaco­dynamics of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) has not been studied but data on the rapid-acting component(NovoLog®) show no significant effect. Some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure. Careful glucose monitoring and dose adjustments of insulin, including NovoLog® Mix 50/50, may be necessary in patients with he­patic dysfunction (see PRECAUTIONS, Hepatic Impairment).

Pregnancy - The effect of pregnancy on the pharmacokinetics and pharmacodynamics of NovoLog® Mix 50/50 has not been studied (see PRECAUTIONS, Pregnancy).

Smoking- The effect of smoking on the pharmacokinetics and pharmacodynamics of NovoLog® Mix 50/50 has not been studied.

Last reviewed on RxList: 9/30/2008
This monograph has been modified to include the generic and brand name in many instances.

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