Novomix 30 100 u/mL

The effect of age on the pharmacokinetics and pharmacodynamics of NovoMix 30 has not been studied.

Mean Serum Insulin Concentration Following a Single Subcutaneous Dose (0.2 U/kg body weight) of NovoMix 30 (solid line) and Biphasic Human Insulin 30/70 (hatched line) in Healthy Subjects

The effect of smoking on the pharmacokinetics and pharmacodynamics of NovoMix 30 has not been studied.

In a 3 month, multicentre, open-labelled, randomized, parallel group study, NovoMix 30 was as effective as biphasic human insulin 30/70 (Novolin ge 30/70) in long-term glycemic control, based on HbA_1C levels. Mealtime blood glucose increment averaged over the three main meals was statistically significantly different (29% lower) in the NovoMix 30 group (p<0.02) and statistically significant differences (approximately 1 mmol/L lower) were observed in mean blood glucose levels after breakfast, before lunch, after dinner and at bedtime (p<0.02-0.05). Improvements in postprandial glycemic control did not increase the risk of hypoglycemia. Patients wishing to continue in an extension of this study were followed for an additional 21 month period on either NovoMix 30 or Novolin ge 30/70. At the end of the 24 month period of treatment, glycemic control, as measured by HbA_1c, was similar in the two groups.

With similar levels of glycemic control (as assessed by HbA_1c), the number and rate of hypoglycemic episodes was similar in patients with Type 1 diabetes. However, for patients with type 2 diabetes, those treated with NovoMix 30 had a lower frequency of major hypoglycemia than those receiving Novolin ge 30/70 and during the last six months of the study, no patients treated with NovoMix 30 experienced major hypoglycemia.

In a clinical trial, 61 subjects with type 2 diabetes received a single dose of NovoMix 30, Humalog Mix25 and Novolin ge 30/70 (insulin, human biosynthetic) on three separate occasions in a cross-over trial. Postprandial glycemic control, as assessed by the 5-hour post meal serum glucose excursion was statistically significantly improved (a 10% reduction, p<0.05) with NovoMix 30 over Humalog Mix25 and Novolin ge 30/70 (a 17% reduction, p<0.001). For NovoMix 30 versus Novolin ge 30/70, maximum glucose concentration was reduced and occurred earlier. Compared to Humalog Mix25 there was a shorter time to maximum glucose concentration.

One hundred and fifty-one type 2 patients inadequately treated with oral diabetes medication (metformin with/without insulin secretagogues) were entered into a clinical trial. During the first 4 weeks of the trial, patients were titrated to target with metformin only. Those patients who did not achieve fasting glycemic levels within the target range of 5-7 mmol/L (n=140) were initiated on insulin therapy in a randomized fashion to receive one of three insulin treatment regimens once a day in combination with the metformin therapy: NovoMix 30 (at dinner), Novolin ge 30/70 (at dinner) or Novolin ge NPH (before bed). There were no statistically significant differences between treatment groups for long term glycemic control; mean HbA_1c levels were reduced from baseline by 1.1-1.3% with 12 weeks of treatment. There was no significant difference in reporting of hypoglycemic events among the three groups although fewer patients reported nocturnal hypoglycemic events in the NovoMix 30 group than in the other groups. At the end of the study, the final fasting plasma glucose fell within target range (5-7 mmol/L) for 9 subjects in the NovoMix 30 group, 9 subjects in the Novolin ge NPH group and 8 subjects in the Novolin ge 30/70 group. The mean decrease in HbA_1c values experienced by these subjects (−2.3%, −1.9% and −1.8% respectively) were greater than observed for the total study population.

Metformin-treated patients with type 2 diabetes (n=341) were randomized to receive NovoMix 30 monotherapy BID, NovoMix 30 BID with existing metformin or sulphonylurea therapy with existing metformin. In the total population, the mean difference in HbA_1c levels was statistically significant only for subjects receiving NovoMix 30 plus metformin versus NovoMix 30 monotherapy (p=0.004). Mean decrease in HbA_1c during the study was 1.5-1.8% in all groups. In 193 patients with poorly controlled diabetes at the start of the trial (HbA_1c ≥9.0%), the mean difference in HbA_1c was statistically significant in the NovoMix 30 plus metformin group versus the NovoMix 30 monotherapy group (p=0.037) and the sulphonylurea plus metformin group (p=0.033) after 16 weeks of treatment. Mean HbA_1c decrease during the study was 1.9 to 2.4% in all groups.

The efficacy and safety of NovoMix 30 in NovoMix 30 FlexPen was compared with Humalog Mix25 in Humalog Mix25 Pen in 132 insulin-treated patients with type 2 diabetes in a open-label, two-period crossover design trial. Following a 2-week run-in period on NovoMix 30, patients began the first 12-week treatment period on either NovoMix 30 or Humalog Mix25. At the last visit of the first treatment period, the patients completed pen device questionnaires and the WHO Diabetes Treatment Satisfaction Questionnaire (DTSQ) and then changed to the alternate insulin treatment. At the end of the 2^nd 12-week treatment period, patients again completed the pen device questionnaires, the DTSQ and a comparative questionnaire asking which device they would prefer to continue to use after the trial. Treatment with NovoMix 30 and Humalog Mix25 were comparable with respect to HbA_1c, prandial blood glucose increment, postprandial blood glucose and episodes of hypoglycemia at the end of the trial. Patient treatment satisfaction, as measured by DTSQ was similar for both groups. For the device specific questionnaires, NovoMix 30 FlexPen was evaluated as slightly superior to Humalog Mix25 Pen in 15 of 16 device features assessed (all p<0.001). Approximately 75% of patients preferred to continue with NovoMix 30 FlexPen after the trial was completed.

Insulin aspart has a low binding to plasma proteins, 0-9%. After subcutaneous administration, insulin aspart 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 ethnic origin on the pharmacokinetics and pharmacodynamics of NovoMix 30 has not been studied.

The effect of gender on the pharmacokinetics and pharmacodynamics of NovoMix 30 in diabetic patients has not been studied.

The safety and efficacy of NovoMix 30 were compared to biphasic human insulin 30/70 (BHI 30) in a double-blind crossover trial in 54 children, aged 6-12 years. The incidence of all hypoglycemic episodes was significantly lower for NovoMix 30 than for BHI 30 by approximately 10%. No safety concerns were raised during the trial. However, after 12 weeks of treatment it could not be demonstrated, that treatment with NovoMix 30 was non-inferior to treatment with BHI 30 with respect to HbA_1c and serum fructosamine. The data available are inadequate to establish the effectiveness in children.

In a randomized, double-blind, two-way cross-over trial comparing NovoMix 30 and biphasic human insulin 30/70 in patients with type 2 diabetes, the therapeutic response was evaluated following two 2-week treatment periods where insulin was administered in a twice daily dose regimen; immediately before breakfast and dinner. The shape of the 24-hour total serum glucose concentration-time profiles were statistically significantly different between treatments over time (see Figure 3). Although there was no difference detected between treatments with respect to average serum glucose levels over 24 hours, the estimated mean time-action curves shown below indicate that postprandial glucose control was superior with NovoMix 30 compared to biphasic human insulin 30/70, following dinner and breakfast but higher after lunch.

Estimated Mean 24-hour Serum Glucose Profiles: See Figure 3.

The effect of obesity on the pharmacokinetics and pharmacodynamics of NovoMix 30 has not been studied.

The rapid absorption characteristics of NovoRapid are maintained by NovoMix 30. The insulin aspart in the soluble component of NovoMix 30 is absorbed more rapidly from the subcutaneous layer than regular soluble human insulin. The remaining 70% is in crystalline form as insulin aspart protamine that has a prolonged absorption profile after subcutaneous injection.

The relative bioavailability of NovoMix 30 compared to premixed human insulin 30/70 indicates that they are absorbed to similar degrees.

The maximum serum insulin concentration (C_max) for NovoMix 30 is, on average, 50% higher than with biphasic human insulin 30/70 (p=0.000). The time to maximum concentration (T_max) is, on average, half that for biphasic human insulin 30/70 (p=0.000). In healthy volunteers, a mean maximum serum concentration of 23.4±5.3 mU/L was reached about 60 minutes after a subcutaneous dose of 0.2 U/kg body weight versus 15.5±3.7 mU/L at about 130 minutes for biphasic human insulin 30/70. The mean half life (t_½) of NovoMix 30, reflecting the absorption rate of the protamine bound fraction, was about 8-9 hours. Serum insulin levels returned to baseline about 15-18 hours after a subcutaneous dose. In type 2 diabetic patients, the maximum concentration was reached about 95 minutes after dosing.

Pharmacokinetic Profiles of NovoMix 30 and Biphasic Human Insulin 30/70: See Figure 1.

NovoMix 30 (30% soluble insulin aspart and 70% insulin aspart protamine crystals) is a dual-release human insulin analogue suspension containing 30% soluble insulin aspart. This has a rapid onset of action, thus allowing it to be given closer to a meal when compared to soluble human insulin. The crystalline phase (70%) consists of insulin aspart protamine, which has an activity profile similar to that of human NPH insulin.

The pharmacodynamic response to a single dose of 0.3 U/kg NovoMix 30 and premixed human insulin 30/70 was investigated in 24 healthy subjects using the hyperinsulinaemic euglycemic clamp method. NovoMix 30 shows a significantly greater metabolic effect in the first 4 hours after subcutaneous injection than the premixed human insulin 30/70 (see Figure 2). When NovoMix 30 is injected subcutaneously, the onset of action will occur within 10 to 20 minutes of injection. The maximum effect is exerted between 1 and 4 hours after injection. The duration of action is up to 24 hours.

Concomitant use of other drugs may influence insulin requirements. The following substances may reduce the insulin requirements: oral hypoglycemic agents (OHA), octreotide, monoamine oxidase inhibitors (MAOI), non-selective beta adrenergic blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates, alcohol, and anabolic steroids.

Other drugs may increase insulin requirements: oral contraceptives, thiazides, glucocorticosteroids, thyroid hormones, sympathomimetics and danazol.Beta blocking agents may mask the symptoms of hypoglycemia. Alcohol may intensify and prolong the hypoglycemic effect of insulin.

The data available are inadequate to establish the efficacy of NovoMix 30 in children (see Special Populations, Children and adolescents).

Reproduction studies have been performed in rats and rabbits at doses up to 16-32 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to insulin aspart . There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Although there are no clinical studies of the use of NovoMix 30 in pregnancy, published studies with human insulin suggest that optimizing overall glycemic control, including postprandial control, before conception and during pregnancy improves fetal outcome. Although the fetal complications of maternal hyperglycemia have been well documented, fetal toxicity also has been reported with maternal hypoglycemia. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. Careful monitoring of the patient is required throughout pregnancy. During the perinatal period, careful monitoring of infants born to mothers with diabetes is warranted.

Insulin antibodies may develop during treatment with insulin. Insulin antibody production was fmonitored during the clinical development program for NovoMix 30. A transitory 11.2% increase in cross-reactive antibodies observed during the initial 3 months of treatment with BIAsp 30 in the phase III trial was followed by a significant decrease from month 3 to 12. This decrease was maintained between months 12 and 24, where concentrations were constant at about 5 absolute percentage points above baseline for the type 2 diabetic subjects and 7.02% for the total population (type 1 and 2 diabetic subjects). No relationship between cross-reactive antibody level and metabolic control, insulin dose requirements or adverse events has been observed.

There is no information on teratogenicity of insulin aspart in humans. In rabbit trials, insulin aspart did not exert any direct adverse effect on fertility, mating performance, reproductive capacity or embryo-fetal development and did not differ from human insulin.

There is no experience of treatment with insulin aspart in patients with hepatic impairment. As with other insulins, NovoMix 30 requirement may need to be adjusted in patients with hepatic impairment.

When patients are transferred between different types of insulin products, the early warning symptoms of hypoglycaemia may change or become less pronounced than those experienced with their previous insulin. Transferring a patient to a new type or brand of insulin should be done under strict medical supervision. Changes in strength, brand, type, species (animal, human, human insulin analogue), and/or method of manufacture may result in the need for a change in dosage. Patients taking NovoMix 30 may need a change in dosage from that used with their usual insulins. If an adjustment is needed, it may be done with the first dose or during the first few weeks or months.

There is no experience of treatment with insulin aspart in patients with renal impairment. As with other insulins, NovoMix 30 requirement may be reduced in patients with renal impairment.

NovoMix 30 should not be mixed with any other insulin product.

It is unknown whether NovoMix 30 is excreted in significant amounts in human milk. For this reason, caution should be exercised when NovoMix 30 is administered to a nursing mother. Patients with diabetes who are lactating may require adjustments in insulin dose, meal plan or both.

As with all insulins, the duration of action of NovoMix 30 (30% soluble insulin aspart and 70% insulin aspart protamine crystals) may vary in different individuals or in the same individual according to dose, injection site, blood flow, temperature and level of physical activity.

Hypokalemia is among the potential clinical adverse effect associated with the use of all insulins. This potential clinical adverse effect may be relevant in patients who are on potassium lowering drugs.

Stress or illness may change insulin requirements. In these instances, patients should contact their physician and carefully control their blood glucose.

As with all insulin therapy the need for regular blood glucose self-monitoring should be considered when using NovoMix 30 to obtain optimal glycemic control.

Systemic allergic reaction have not been reported during the clinical development of NovoMix 30. Systemic allergic reactions have rarely occurred with NovoMix 30 as with other insulin treatment. These reactions may be characterized by a generalized rash (with pruritus), shortness of breath, wheezing and drop in blood pressure. Severe cases of generalized allergy including anaphylactic reaction may be life threatening.

In certain cases (long duration of diabetes, diabetic nerve disease, intensified diabetes control, or use of medications such as beta blocking agents), the nature and intensity of early warning symptoms of hypoglycemia may change or be less pronounced.

Hypoglycemia is the most frequently occurring undesirable effect of insulin therapy. Such reactions following treatment with NovoMix 30 are mostly mild and easily managed.

Severe hypoglycemia can result in temporary or permanent impairment of brain function and death.

Changes in insulin therapy or changes in life style (i.e. diet, exercise/physical activity) may require a change in dosage. Inadequate dosing or discontinuation of insulin treatment, especially in type 1 diabetes, may lead to hyperglycemia and diabetic ketoacidosis. Severe sustained hyperglycemia may result in diabetic coma and death.

Glucose monitoring is recommended for all patients with diabetes.

The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may constitute a risk in situations where these abilities are of special importance (e.g., driving a car or operating machinery).

As with other insulins, patients may experience redness, swelling or itching at the site of injection. These minor reactions usually resolve in a few days to a few weeks. They may occur if the injection is not properly made, or if the patient is allergic to the insulin or any excipients. Few local injection site reactions were observed with NovoMix 30 in the clinical development program and there was no difference in frequency when compared to human insulin.

Patients should be informed about potential advantages and disadvantages of NovoMix 30 therapy including the possible side effects. Patients should also be offered continued education and advice on insulin therapies, life-style management, self-monitoring, complications of insulin therapy, timing of dosage, instruction for use of injection devices and storage of insulin.

The need for regular blood glucose self-monitoring should be considered when using any insulin therapy to obtain optimal glycemic control.

Female patients should be advised to discuss with their physician if they intend to or if they become pregnant.

Small elevations in alkaline phosphatase were observed in patients treated with NovoMix 30 in controlled clinical trials. Some patients initially had normal levels of alkaline phosphatase, which subsequently rose above normal range. There have been no clinical consequences of these findings.

Hypoglycemia and Treatment of Overdosage: Overdose may cause hypoglycemia. Omission of a meal or unplanned strenuous physical exercise may lead to hypoglycemia. Symptoms of hypoglycemia may occur suddenly. They may include cold sweat, cool pale skin, fatigue, nervousness or tremor, anxious feeling, unusual tiredness or weakness, confusion, difficulty in concentration, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may be fatal.

Mild episodes of hypoglycemia can be treated by oral administration of glucose or sugary products. It is therefore recommended that patients with diabetes always carry some sugar candy.

Severe hypoglycemic episodes, where the patient has become unconscious, can be treated with glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person or glucose given intravenously by a medical professional. Glucose must also be given intravenously if the patient does not respond to glucagon within 10 to 15 minutes. Upon regaining consciousness, administration of an oral carbohydrate is recommended for the patient in order to prevent relapse.

Patients being initiated on insulin for the first time can be started on NovoMix 30 in the same manner as they would be on animal-source or human insulin.

When patients are transferred from other insulin to NovoMix 30, the change should be made as directed by the physician.

In clinical trials of NovoMix 30, patients were transferred on a unit to unit basis from human premixed 30/70 or human NPH to NovoMix 30 with doses subsequently adjusted according to individual patient needs.

NovoMix 30 is a white suspension. The carton contains a package leaflet with instructions for use and handling. The necessity of properly resuspending NovoMix 30 immediately before use should be stressed to the patient. The resuspended liquid must appear uniformly white and cloudy. NovoMix 30 should not be used after it’s expiration date. NovoMix 30 should not be injected intravenously.

In patients with diabetes mellitus, optimized metabolic control effectively delays the onset and slows the progression of late diabetic complications. Optimized metabolic control, including glucose monitoring is therefore recommended.

NovoMix 30 (30% soluble insulin aspart and 70% insulin aspart protamine crystals) is administered subcutaneously in the abdominal wall, the thigh, the upper arm or the buttock. Care should be taken to avoid entry into a blood vessel. Injection sites should be rotated within the same region. As with all insulins, the duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity.