SUMMARY PRODUCT INFORMATION 3 DESCRIPTION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 9 DRUG INTERACTIONS 13 DOSAGE AND ADMINISTRATION 14 HYPOGLYCAEMIA AND OVERDOSAGE 15 ACTION AND CLINICAL PHARMACOLOGY 16 STORAGE AND STABILITY 21 DOSAGE FORMS, COMPOSITION AND PACKAGING 22

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION 23 CLINICAL TRIALS 24 DETAILED PHARMACOLOGY 29 REFERENCES 33

PART III: CONSUMER INFORMATION

NovoRapid(r)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

DESCRIPTION

NovoRapid(r) NovoRapid(r) NovoRapid(r) NovoRapid(r)

(insulin aspart) is a unique human insulin analogue of rDNA origin that rapidly lowers blood glucose.

is homologous with regular human insulin with the exception of a substitution of the amino acid proline for aspartic acid in position B28. The substitution of the amino acid proline with aspartic acid at position B28 in

is therefore more rapidly absorbed from the subcutaneous layer compared to regular human insulin. The insulin is derived from the fermentation of genetically modified yeast cells (recombinant DNA origin, Saccharomyces cerevisiae). The fermentation, isolation, conversion and purification of insulin aspart are equivalent to the procedures used for production of genetically engineered human insulin.

CONTRAINDICATIONS

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Due to its faster onset of action, NovoRapid(r) should be given immediately before the meal. The injection should not be more than 5-10 minutes before the start of a meal. GeWnehreanl necessary, NovoRapid(r) may be given immediately after the meal.

As with all insulins, the duration of action of NovoRapid(r) may vary in different individuals or in the same individual according to dose, injection site, blood flow, temperature and level of physical activity3. NovoRapid(r) differs from regular human insulin by its rapid onset and shorter duration of action. As a result of the fast onset of action, the injection of NovoRapid(r) should immediately be followed by a meal. As a result of the short duration of action of NovoRapid(r), patients with diabetes may also require a longer-acting insulin to maintain adequate glucose control. 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 drugs4. Stress or illness may increase insulin requirements. In these instances, patients should contact their physician and carefully control their blood glucose3. Any change of insulin dose should be made cautiously and only under medical supervision. Transferring a patient to a new type or brand of insulin should be done under strict medical supervision. Changes in insulin strength, brand type (e.g., regular, NPH, analogue), species (animal, human), or method of manufacture (rDNA versus animal-source insulin) may result in the need for a change in dosage. Patients taking NovoRapid(r) may need a change in dosage from that used with their previous insulin. Concomitant illness, especially infections, usually increases the patient's insulin requirements.

Hypoglycemia

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 pronounced5. Hypoglycemia is the most frequently occurring undesirable effect of insulin therapy. Such reactions following treatment with NovoRapid(r) are mostly mild and easily managed. While the frequency of hypoglycemia observed in clinical trials is similar to that observed with regular human insulin, Clinical trials in patients with Type 1 diabetes have demonstrated a reduced risk of nocturnal hypoglycemia with insulin aspart compared with soluble human insulin.23, 24 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. 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).

Hyperglycemia

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.

The pharmacokinetics of NovoRapid(r) did not change in patients with mild (Mean Child Pugh Score: 5.7), moderate (Mean Child Pugh Score:7.3) or severe (Mean Child Pugh Score: 10.2) hepatic impairment as compared to subjects with normal hepatic function (Mean Child Pugh Score: 0). (Holmes). As with other insulins, NovoRapid(r) requirement may need to be adjusted in patients with hepatic impairment.

Insulin antibodies may develop during treatment with insulin. In the clinical development program, insulin aspart-specific, regular human insulin-specific and cross reactive antibodies were analyzed. Antibody production was monitored in 665 patients for 12 months. After a transient statistically significant increase in cross-reacting antibodies from baseline to 3 months for NovoRapid(r) compared to human insulin, cross-reacting antibody levels returned to baseline levels in the NovoRapid(r) group and were not different from the human insulin group. No adverse effects could be attributed to patients producing cross reactive antibodies as compared to those who did not. There was no correlation between the extent of antibody formation and the insulin dose needed, level of glycemic control attained or adverse event reporting after 12 months treatment. No systemic allergic reactions were observed. In a clinical study on the use of NovoRapid(r) (n=157) during pregnancy in patients with type 1 diabetes, mean levels of antibodies specific to NovoRapid(r) were low (<3%). Variability between subjects was up to 14% for NovoRapid(r). The majority of antibodies were cross reacting. There was no observable increase in antibodies with NovoRapid(r) treatment from baseline to the end of the third trimester. Similar observations were found in cord blood. Mean levels of antibodies specific to NovoRapid(r) were low (<1%). The majority of insulin antibodies were cross-reacting, and variability between subjects was up to 17% for NovoRapid(r) specific antibodies. Levels of antibodies in cord blood seemed to correlate with maternal antibodies which are consistent with a transfer of maternal cross-reacting insulin antibodies across the placenta. The same pattern was observed for NovoRapid(r) specific antibodies. In a clinical trial including 14 women with gestational diabetes assigned to treatment with NovoRapid(r) mean levels of antibodies specific to NovoRapid(r) remained relatively low (les than 0.5% binding). See also WARNING AND PRECAUTIONS, Sexual Function/Reproduction and Special Populations, Pregnant Women, ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Pregnancy clinical trials; and Part II, SCIENTIFIC INFORMATION, CLINICAL TRIALS, Type 1 Diabetes.

The pharmacokinetics of NovoRapid(r) did not change in patients with mild (mean Clcr 60.0 mL min-1 ), moderate (mean Clcr: 35.7 mL min-1 ) and severe (mean Clcr : 23.5 mL min-1 ) as compared to patient with normal renal function Clcr:> 99.8 mL min-1 ). The degree of renal impairment does not affect the pharmacokinetics variable of NovoRapid(r) (Holmes). As with other insulins, NovoRapid(r) requirement may be reduced in patients with renal impairment. NovoRapid(r) requirement may need to be adjusted in patients with severe renal impairment.

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

Pregnancy:

Congenital anomalies are three to four times more prevalent in diabetic pregnancy than in non- diabetic pregnancies and with a two fold higher mortality from major cardiovascular anomalies In a clinical trial of 157 pregnant women with type 1 diabetes treated with NovoRapid(r) 10 congenital malformations were reported in 9 (5.7%) subjects treated with NovoRapid(r). Cardiac anomalies were reported (n=7) mainly septal defects (n=4). Additional reports in patients treated with NovoRapid(r) were one each of central nervous system anomaly, ankyloglossia and feta disorders. Of the women who received NovoRapid(r), fetal exposure throughout the entire pregnancy occurred in 44 women. One child exposed to NovoRapid(r) had an anomaly neck edema resulting in fetal loss. A clinical trial of 14 women with gestational diabetes who received treatment with NovoRapid(r). Two infants in each group had abnormal findings, all findings were felt to be unrelated to the treatment. See also WARNINGS AND PRECAUTIONS, Immune and Special Populations, Pregnant Women; ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Pregnancy clinical trials; and Part II, SCIENTIFIC INFORMATION, CLINICAL TRIALS, Type 1 Diabetes.

Local allergic reaction

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 excipients6. Few local injection site reactions were observed with NovoRapid(r) in the clinical development program and there was no difference in frequency when compared to regular human insulin.

NovoRapid(r) can be used in pregnant women with type 1 diabetes if clinically indicated. It is essential for patients with type 1 diabetes to maintain good metabolic control before conception and throughout pregnancy. Insulin requirements usually decrease during the first trimester and increase during the second and third trimesters. Patients should be advised to inform their health care professional if they are pregnant or are contemplating pregnancy. Careful monitoring of glucose control is essential in these patients. A study was conducted in 157 pregnant women with type 1 diabetes treated with NovoRapid(r). Two third (n = 113) of the enrolled patients were already pregnant when they entered the study. Because only one third (n=44) of the patients were enrolled before conception, the sample size was not large enough to evaluate the risk of congenital malformations. A1C was evaluated during the study as well as the incidence of hypoglycemia. (See also, Clinical Trial Adverse Drug

Pregnancy clinical trials and Part II, SCIENTIFIC NFORMAITON, CLINCIAL TRIALS, TYPE 1 Diabetes).

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 NovoRapid(r).

Nursing Women:

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

Pediatrics (2 - 17 years of age)

The pharmacokinetic properties of NovoRapid(r) (insulin aspart injection) and regular human insulin were investigated in 18 children (6 -12 years, n = 9) and adolescents (13 -17 years, n = 9) with type 1 diabetes. The relative difference in pharmacokinetics and pharmacodynamics in type 1 diabetic children and adolescents between NovoRapid(r) and regular human insulin correlated well with those in healthy adult subjects and Type 1 diabetic adults. The efficacy and safety of NovoRapid(r) were compared to regular human insulin, both supplemented with NPH insulin, in a 24-week crossover (two 12-week treatments), randomized trial in children (age 2-6, n=25) with type 1 diabetes. NovoRapid(r), injected either shortly before meal or immediately after a meal, produced the same effects with respect to postprandial blood glucose control (p=0.5180) and to overall glycemic control (as measured by A1C levels, 7.7 +- 0.23% vs 7.56 +- 0.25%, 0.111 (95% CI -0.113:0.336) as regular human insulin, injected 30 minutes before a meal. The safety profile was comparable to that of regular human insulin and did not appear to differ from that of NovoRapid(r) in adults with type 1 diabetes. In addition, as compared to regular human insulin, NovoRapid(r) did not increase the frequency and risk of hypoglycemia [RR 1.06 (95% CI: 0.96-1.17; p=0.225)]. In another trial, the efficacy and safety of NovoRapid(r) were compared to insulin lispro and regular human insulin in a 24-week, randomized, open label study in 378 children (6-18 years of age) with type 1 diabetes. NPH insulin was administered as basal insulin. Baseline means A1C values for NovoRapid(r), lispro and regular human insulin were 8.3 +- 1.2%, 8.4% +- 1.2% and 8.3 +- 1.2%, respectively. At the end of the study, patients had man A1C values of 8.4 +- 1.4%, 8.2 +- 1.2% and 8.3 +- 1.4%, respectively. The changes from baseline were not significantly different among the groups. NovoRapid(r) demonstrated similar, postprandial, blood glucose levels as lispro. The blood glucose levels after lunch and dinner decreased significantly with NovoRapid(r) than with regular human insulin (lunch: 10.2 +- 4.5 mmol/L vs. 11.2 +- 4.7mmol/L, respectively; p=0.009; dinner: 10.5 +- 4.4 mmol/Lvs.11.6 +- 4.8mmol/L, respectively; p=0.003. Furthermore, NovoRapid(r) did not increase the risk of hypoglycemia and had a safety profile comparable to both regular human insulin and lispro.

Geriatrics (> 50 years of age):

In the clinical development program, 226 patients aged 50 years and older (including 35 patients above the age of 65) were treated with NovoRapid(r) for up to 6 months. No differences in dose, efficacy or adverse events were observed between these patients and younger population. Gender - There was no significant difference in pharmacokinetics in a trial in Type 2 diabetic patients. No significant difference in efficacy, as assessed by A1C, was found between genders in a trial in Type 1 diabetic patients.

The influence of obesity and/or subcutaneous fat thickness on the pharmacokinetics and glucodynamics of NovoRapid(r) has not been studied. (delete the previous sentence) Patients with a body mass index (BMI) up to 40kg/m2 were treated with NovoRapid(r). No difference was observed in efficacy and safety compared to leaner patients.13

There was no difference in efficacy in terms of blood glucose control as measured by A1C or safety in terms of adverse events between African Americans, Hispanics and Caucasian patients.

As with all insulin therapy, the need for regular blood glucose self-monitoring should be considered when using NovoRapid(r) to obtain optimal glycemic control. Periodic measurement of glycosylated hemoglobin is recommended for the monitoring of long-term glycemic control. If patient is pregnant, careful monitoring of the patient is required throughout pregnancy. During the perinatal period, careful monitoring of infants born to mothers with diabetes is warranted.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The most frequently seen undesirable effect in insulin-treated patients is change in blood glucose levels. From clinical investigations, it is known that major hypoglycaemia, defined as need for assistance in treatment, is common (>1/10) in well-controlled patients. Based on post-marketing experience adverse events including hypoglycaemia are rare (>1/10 000 and <1/1000) during use of Novo Nordisk human insulin products.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. The safety profile of NovoRapid(r) observed in clinical trials is similar to the safety profile reported for Novo Nordisk human insulin products. Frequencies of adverse drug reactions from clinical trials, which by an overall judgement are considered related to NovoRapid(r) are listed below. The frequencies are defined as: Uncommon (>1/1,000, <1/100) and rare (>1/10,000, <1/1,000). Isolated spontaneous cases are presented as very rare defined as (<1/10,000).

Immune system disorders:

Uncommon:Urticaria, rash, eruptions Very Rare:Anaphylactic Reactions: Symptoms of generalised hypersensitivity may include generalised skin rash, itching, sweating, gastrointestinal upset, angioneurotic oedema, difficulties in breathing, palpitation and reduction in blood pressure. Generalised hypersensitivity reactions are potentially life threatening.

Nervous system disorders:

Rare:Peripheral neuropathy Fast improvement in blood glucose control may be associated with a condition termed acute painful neuropathy, which is usually reversible.

Eye disorders

Uncommon:Refraction disorder Refraction anomalies may occur upon initiation of insulin therapy. These symptoms are usually of transitory nature. Uncommon:Diabetic retinopathy Long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy. However, intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with worsening of diabetic retinopathy.

Skin and subcutaneous tissue disorders

Uncommon:Lipodystrophy Lipodystrophy may occur at the injection site as a consequence of failure to rotate injection sites within an area. Uncommon:Local hypersensitivity Local hypersensitivity reactions (redness, swelling and itching at the injection site) may occur during treatment with insulin. These reactions are usually transitory and normally they disappear during continued treatment.

General disorders and administration site conditions

Uncommon:Oedema Oedema may occur upon initiation of insulin therapy. These symptoms are usually of transitory nature.

Pregnancy clinical trials

In a clinical trial comparing safety and efficacy of NovoRapid(r) to insulin human in the treatment of pregnant women with type 1 diabetes (322 exposed pregnancies 157 to insulin aspart 165 to human insulin) the adverse event profiles were similar in subjects receiving NovoRapid(r) and those receiving regular human insulin with respect to incidence and severity. Most adverse events were mild or moderate in severity. With the exception of obstetric complications, the adverse event profile was similar in subjects during pregnancy and outside pregnancy. There were no differences in the incidence of obstetric complications between treatment groups.

Maternal Serious adverse events with possible or probable relationship to trial drugNovoRapid(r)

: Serious adverse events with possible or probable relation to trial drug were reported with

or regular human insulin in >1% of subjects: hypoglycemia, inadequate control of diabetes, hypoglycemic coma.

The following maternal serious adverse events with possible or probable relationship to trial drug were reported at an incidence of <1% for NovoRapid(r): spontaneous abortion, missed abortion and cesarean section. See also WARNINGS AND PRECAUTIONS, Immune, and Sexual Functions/reproduction and Special populations; Pregnant Women; and Part II, SCIENTIFIC INFORMATION, CLINCIAL TRIALS, Type 1 Diabetes.

Less Common Clinical Trial Adverse Drug Reactions (<1%):

In addition, the following adverse events were reported at an incidence of <1% for NovoRapid(r) regardless of drug relationship. Breech presentation, complication of delivery, hyperemesis gravidarum, HELLP syndrome, premature labour, ketoacidosis, ketonuria, acute bronchitis, hepatitis C, tonsillitis, tracheitis, uterine atony, asthenia, generalized oedema, contusion, obstetric procedure complication. No clinically relevant differences were observed for any of the laboratory assessments, vital signs, ECG, or urine albumin/creatinine. In each treatment group (NovoRapid(r) and insulin human), 3 malformations resulted in fetal loss or death of the child. Serious adverse events were reported in 36% of children in the NovoRapid(r) group and 29% of children in the regular human insulin group, the child adverse events profile was similar to that normally seen in children of diabetic mothers 33.6% of children in the NovoRapid(r) group and 39.7% in the regular human insulin group experienced hypoglycemia leading to treatment (oral or intravenous glucose/dextrose or early feeding). The most frequently reported adverse event with a frequency of over 1% in the clinical trial of 27 women with gestational diabetes the most commonly reported reaction was upper respiratory tract infection, as well as hypoglycemic reactions. In the gestational pregnancy study 71% of women in the insulin aspart group and 69% of women in the regular human insulin group experienced a symptomatic hypoglycemic episode. No major hypoglycemic episodes were reported in this study. Two infants in each group had abnormal findings, all findings were felt to be unrelated to the treatment. In the NovoRapid(r) group, one fetal death occurred in utero due to umbilical cord strangulation at week 40, and one small pneumothorax and tachypnea which resolved the following day.

Post-Market Adverse Drug Reactions:

Adverse Drug Event Overview for a Post-Marketing CSII Trial

A 4 month post-marketing study in 511 subjects with type 1 and insulin-requiring type 2 diabetes mellitus was conducted as a preference trial to assess the treatment satisfaction of NovoRapid(r) and insulin lispro during CSII pump therapy. Adverse drug events were recorded when spontaneously reported by the patients in the study. The only adverse drug event reported at an incidence >= 1% was upper respiratory tract infection (incidence of 1.3% in the NovoRapid(r) group).

Less Common Adverse Drug Events (<1%) in a Post-Marketing CSII Trial

In addition, the following adverse drug events were reported at an incidence of <1% for NovoRapid(r) or insulin lispro in this study (in more than 1 patient in each treatment group), regardless of drug relationship.

Gastrointestinal Disorders:

vomiting, nausea

Infections and Infestations:

viral infection, urinary tract infection, sinusitis, onychomycosis, nasopharyngitis, bronchitis

Metabolism and Nutrition Disorders: Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders:

hypoglycemia, hyperglycemia, diabetic ketoacidosis

pain in extremity, back pain, arthralgia

neuropathy

Respiratory, Thoracic and Mediastinal Disorders:

nasal congestion

The following serious adverse events were reported in more than 1 patient but at an incidence of < 1% for NovoRapid(r) in Study 2190:

Metabolic and nutritional disorders:

hypoglycemia (4 episodes) and diabetic ketoacidosis (2 episodes).

Hypoglycemia as an Adverse Drug Reaction in a Post-Marketing CSII Trial

The reporting of hypoglycemia was not a specific safety endpoint in this trial. Hypoglycemic episodes were recorded only if spontaneously reported by the subject as adverse drug reactions. Consequently, data on hypoglycemia is limited from this study. There were only seven episodes of hypoglycemia reported during the four-month trial with over 500 patients. As such, the incidence of hypoglycemia was calculated to be <1% of the patients treated with either NovoRapid(r) or insulin lispro and does not reflect real-life occurrence of hypoglycemia in diabetes patients.

DRUG INTERACTIONS

Mixing of insulins

If NovoRapid(r) (insulin aspart) is mixed with an intermediate-acting or long-acting insulin, NovoRapid(r) should be drawn into the syringe first. The injection should be made immediately after mixing. Pharmacodynamic trials conducted in pigs showed bioequivalence between separate injections of NovoRapid(r). These included neutral protamine regular human insulin, a mix of

NovoRapid(r)

and neutral protamine regular human insulin when injected 5 minutes after mixing.

The effect of mixing NovoRapid(r) with either animal-source insulins or human insulin preparations produced by other manufacturers have not been studied. This practice is not recommended.

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.

Please refer to ACTION AND CLINICAL PHARMACOLOGY, Mechanism of Action and DOSAGE AND ADMINISTRATION for interactions with food and timing of food consumption, respectively.

The effect of smoking on the pharmacokinetics and pharmacodynamics of NovoRapid(r) has not been studied. However, metabolic control was similar in smokers and non-smokers after 6 months treatment with NovoRapid(r) in the clinical development program. The influence of obesity and/or subcutaneous fat thickness on the pharmacokinetics and glucodynamics of NovoRapid(r) has not been studied. Patients with a body mass index (BMI) up to 40kg/m2 were treated with NovoRapid(r). No difference was observed in efficacy and safety compared to leaner patients. Patients should be informed about potential advantages and disadvantages of NovoRapid(r) (insulin aspart) 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 insulin8. The need for regular blood glucose self-monitoring should be considered when using

NovoRapid(r)

DOSAGE AND ADMINISTRATION

patients being initiated on insulin can be started on NovoRapid(r) in the same manner as they would be on animal-source or human insulin changes for patients being transferred from other insulin to NovoRapid(r) should be made as directed by a physician In clinical trials, patients were transferred on a unit to unit basis from Novolin(r)ge Toronto to NovoRapid(r). The doses of meal-related and basal insulin were then changed according to the patients' needs and local practice.

Due to its faster onset of action, NovoRapid(r) should be given immediately before the meal. The injection should not be more than 5-10 minutes before the start of a meal. When necessary, NovoRapid(r) may be given immediately after the meal. Dosage of NovoRapid(r) is individual and determined, based on the physician's advice, in accordance with the needs of the patient. The individual insulin requirement is usually between - 1.0 units/kg/day. In a meal-related treatment, 50 - 70% of this requirement may be provided by NovoRapid(r) and the remainder provided by an intermediate-acting or long-acting insulin. The dosing of NovoRapid(r) should regularly adjusted according to blood glucose measurements. Adjustment dosage may also be necessary if patients undertake increased physical activity or change their usual diet. Exercise taken immediately after a meal may increase the risk of hypoglycemia.

NovoRapid(r) NovoRapid(r)

(insulin aspart) is administered subcutaneously in the abdominal wall, the thigh, buttocks or the upper arm. Injection sites should be rotated within the same region.

retains its more rapid onset and shorter duration of action irrespective of the injection site used (abdomen, thigh, upper arm). As with all insulins, the duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Never use NovoRapid(r) if it has become viscous (thickened) or cloudy; use it only if it is clear and colourless. NovoRapid(r) should not be used after its expiration date. If NovoRapid(r) is mixed with an intermediate-acting or long-acting insulin, NovoRapid(r) should be drawn into the syringe first. The injection should be made immediately after mixing. NovoRapid(r) should not be mixed with long-acting insulin analogue. The effect of mixing NovoRapid(r) with either animal-source insulins or human insulin preparations produced by other manufacturers have not been studied. This practice is not recommended. 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.8

NovoRapid(r) NovoRapid(r)

(10 mL vial) may be used for Continuous Subcutaneous Insulin Infusion (CSII) in pump systems licensed for insulin infusion. Patients using CSII should be comprehensively instructed in the use of the pump system. The infusion and reservoir set should be changed according to the pump manufacturer's instructions. Patients administering

by CSII must have an alternate insulin delivery device available in case of pump system failure.

HYPOGLYCEMIA AND 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.

ACTION AND CLINICAL PHARMACOLOGY

The primary activity of NovoRapid(r) is the regulation of glucose metabolism. Insulins, including NovoRapid(r), bind to the insulin receptors on muscle and fat cells and lower blood glucose by facilitating the cellular uptake of glucose - and simultaneously inhibit the output of glucose from the liver. Insulin aspart is an analogue of human insulin, in which the amino acid, proline, in position 28, has been replaced by aspartic acid. This modification was designed to target the part of the molecule responsible for self association. Due to charge repulsion, insulin aspart has a reduced tendency to self associate. This causes insulin aspart to be absorbed more rapidly, resulting in faster action. Insulin aspart is designed to be similar to human insulin in all other aspects

NovoRapid(r)

produces a more rapid and more pronounced blood glucose lowering effect than regular human insulin, due to a faster absorption from the injection site.

When administered immediately before a meal, the effect of NovoRapid(r) more closely mimics normal physiological post prandial insulin release than regular human insulin used as replacement therapy. This effect leads to reduced post prandial variability in blood glucose concentration. In patients with diabetes mellitus, postprandial blood glucose levels are identified as a predictor of A1C levels.15, 16, 27. Furthermore, postprandial glucose control is an independent risk factor for morbidity and mortality in diabetics.16,18 This has been demonstrated with regard to overall mortality and cardiovascular disease and death.19,20 Since cardiovascular disease is the most frequent cause of death in a diabetic population, control of postprandial glucose levels is now recognized as an important clinical endpoint of successful diabetic therapy. Optimized metabolic control in diabetic patients effectively delays the onset and slows the progression of late diabetic complications. Optimized metabolic control, including glucose monitoring is therefore recommended8.

NovoRapid(r)

(insulin aspart) produces a more rapid and pronounced blood glucose regulating effect than regular human insulin, due to the fast onset of action.

When insulin aspart is injected subcutaneously, the onset of action occurs within 10-20 minutes of injection. The maximum effect is exerted between 1 and 3 hours after injection. The duration of action is 3 to 5 hours.

Fig. 1 Mean blood glucose levels following a single pre-meal subcutaneous dose (0.15U/kg) of NovoRapid(r) injected immediately before a meal (solid line) or regular human insulin administered 30 minutes before a meal (hatched line) in 22 patients with Type 1 diabetes. The mean serum glucose profiles in the figure above show the superior postprandial glucose control obtained with NovoRapid(r) compared to human insulin during the first 4 hours post dosing. This was confirmed by the significantly lower postprandial glucose excursion (EXC) for NovoRapid(r) than for regular human insulin (p = 0.015).

When given to children NovoRapid(r) showed similar long-term glucose control compared to soluble human insulin.

In NovoRapid(r) substitution of the amino acid profile with aspartic acid at position B28 reduces the tendency to form hexamers as observed with soluble human insulin. NovoRapid(r) is therefore more rapidly absorbed from the subcutaneous layer compared to soluble human insulin. The time to maximum concentration is on average, half of that for soluble human insulin. A mean maximum plasma concentration of 492+-256 pmol/l was reached 40 (interquartile range: 30-40) minutes after a subcutaneous dose of 015 U/kg bodyweight in Type 1 diabetic patients. The insulin concentrations returned to baseline about 4 to 6 hours after dose. The absorption rate was somewhat slower in Type 2 diabetic patients, resulting in a lower Cmax (352+-240 pmol/l) and later tmax [60 (interquartile range: 50-90) minutes]. The intra-individual variability in time to maximum concentration is significantly less for NovoRapid(r) than for soluble human insulin, where the intra-individual variability in Cmax for NovoRapid(r) is larger. Reduced renal or hepatic function does not alter the pharmacokinetics of NovoRapid(r).

Absorption:

NovoRapid(r) NovoRapid(r)

(insulin aspart) has a faster absorption, a faster onset and a shorter duration of action than regular human insulin (see Fig.1 and Fig. 2). The relative bioavailability of

to regular human insulin indicates that the two insulins are absorbed to a similar extent.

In clinical trials in healthy volunteers and Type 1 diabetic patients, NovoRapid(r) consistently reached maximum serum concentration at least twice as fast as regular human insulin. The average median time to maximum serum concentration was 40 to 50 minutes for NovoRapid(r) versus 80 to 120 minutes for regular human insulin. The intra-individual variability in time to maximum concentration was significantly less for NovoRapid(r) than for regular human insulin.1

Fig 2 Mean serum insulin concentration following a single pre-meal subcutaneous dose (0.15U/kg body weight) of NovoRapid

injected immediately before a meal (solid line) or regular human insulin administered subcutaneously 30 minutes before a meal (hatched line) in 22 patients with Type 1 diabetes.

The pharmacokinetics following a single 0.15 U/kg dose of NovoRapid(r) just before a standard meal or of regular human insulin 30 minutes before a standard meal were compared in Type 1 diabetic subjects (Figure 3 above). NovoRapid(r) was rapidly absorbed after s.c. administration. There was a significant difference between Cmax for NovoRapid(r) and regular human insulin (mean maximum concentrations 82.1 mU/l and 35.9 mU/l respectively). The absorption rate was somewhat slower in Type 2 diabetic patients, resulting in a lower Cmax, 352 + 240 pmol/l, and later tmax, 60 minutes. In healthy subjects, the pharmacokinetic differences between NovoRapid(r) and regular human insulin, were maintained independent of the injection site (abdomen, thigh or deltoid). When compared to regular human insulin on an equimolar basis, NovoRapid(r) produces significantly superior control of blood glucose following a meal as assessed by excursion of blood glucose during the first 4 hours after a meal (Fig. 1). When injected subcutaneously into the abdomen, the onset of action will occur from 10 minutes after injection. The maximum effect is exerted between 1-3 hours after subcutaneous injection. The duration of action for NovoRapid(r) is 3 to 5 hours compared to 5 to 8 hours for regular human insulin. In this trial, subjects were clamped from the evening before the trial product administration in order to obtain a blood glucose concentration of 5 to 8 mmol/l. The effect of NovoRapid(r) given in a meal related regimen on 23-hour glucose control was studied in 104 Type 1 diabetic patients. After 4 weeks of treatment, the instances of blood glucose levels outside the normal range (4 to 7 mmol/l or 72 to 126mg/dl) were significantly lower with NovoRapid(r) than with regular human insulin2. The extent of absorption (AUC) and tmax(ins) for NovoRapid(r) were found to be independent of injection site when NovoRapid(r) was administered subcutaneously in the abdomen, deltoid, or thigh. However, Cmax(ins) was statistically significantly higher following injection into the abdomen relative to the thigh.

Distribution:

Insulin aspart has a low binding to plasma proteins, 0-9%. A competitive ligand binding analysis using confluent HepG2 cells explored the relative binding affinities of insulin aspart and human insulin for the insulin receptor. There was no difference in their affinity. The affinity of insulin aspart for the insulin receptor was determined to be 92.2% (95% confidence limits 82.0-103.7%) of that of human insulin using HepG2 cells and to 92% of that of human insulin using solubilised receptors. A very low affinity for the human IGF-1 receptor on HepG2 cells was also demonstrated; 68.8% compared to human insulin and about 1/1000th of the binding affinity of IGF-1 itself. These studies show that insulin aspart has almost identical biological properties to human insulin including affinity for the specific insulin receptor, and similar on- and off-rates at that receptor.

Metabolism:

Long-term metabolic control, assessed by A1C was studied in 882 Type 1 diabetic patients in one trial and 1065 Type 1 diabetic patients in another trial, on a meal-related insulin regimen. With NovoRapid(r), significantly improved long-term metabolic control was obtained compared to regular human insulin after 6 months treatment, the values being 7.78"0.03% for NovoRapid(r) and 7.93"0.05% (p <0.01) for regular human insulin in one trial and correspondingly 7.88"0.03% and 8.00"0.04% (p<0.02) in the other trial. Furthermore, this improvement in glycemic control was achieved without increasing the risk of hypoglycemic events. In 182 Type 2 diabetic patients treated with NovoRapid(r) in a meal-related regimen for 6 months, the pharmacodynamic properties of NovoRapid(r) were shown to be not different than regular human insulin with respect to metabolic control as assessed by insulin dose (meal related and NPH). The degradation products (metabolites) of NovoRapid(r) are assumed to be natural amino acids and peptides, which are subsequently incorporated into host proteins or metabolised, as is the case with human insulin. A number of cleavage (hydrolysis) sites on the human insulin molecule have been proposed; 9 none of the insulin metabolites formed following cleavage are active. 10, 11, 12

Excretion:

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 rapid elimination of NovoRapid(r) is reflected in the return of NovoRapid(r) concentrations to pre-dosing levels within 4 hours after dosing.

Pediatrics:

The pharmacokinetic properties of NovoRapid(r) (insulin aspart) and regular human insulin were investigated in 18 children (6 -12 years, n = 9) and adolescents (13 -17 years, n = 9) with Type 1 diabetes. The relative difference in pharmacokinetics and pharmacodynamics in Type 1 diabetic children and adolescents between NovoRapid(r) and regular human insulin correlated well with those in healthy adult subjects and Type 1 diabetic adults. Insulin aspart was rapidly absorbed in both age groups, with similar tmax as in adults. However, Cmax differed between the age groups, stressing the importance of the individual titration of NovoRapid(r).

Geriatrics:

The pharmacokinetics have not been investigated in the elderly population. In the clinical development program, 226 patients aged 50 years and older (including 35 patients above the age of 65) were treated with NovoRapid(r) for up to 6 months. No differences in dose, efficacy or adverse events were observed between these patients and younger population.

Gender:

Race:

There was no difference in efficacy in terms of blood glucose control as measured by A1C or safety in terms of adverse events between African Americans, Hispanics and Caucasian patients.

Hepatic Insufficiency:

Some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure. In an open-label, single-dose study of 24 patients with Child-Pugh Scores ranging from 0 (healthy volunteers) to 12 (severe hepatic impairment), no correlation was found between the degree of hepatic failure and any NovoRapid(r) pharmacokinetic parameter. Careful glucose monitoring and dose adjustments of insulin, including NovoRapid(r), may be necessary in patients with hepatic dysfunction. See WARNINGS AND PRECAUTIONS, Hepatic.

Renal Insufficiency:

Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. A single subcutaneous dose of NovoRapid(r) was administered in a study of 18 patients with creatinine clearance values ranging from normal to <30 mL/min and not requiring hemodialysis. No apparent effect of creatinine clearance values on AUC and Cmax of NovoRapid(r) was found. However, only 2 patients with severe renal impairment were studied (<30 mL/min). Careful glucose monitoring and dose adjustments of insulin, including NovoRapid(r) on AUC and Cmax of NovoRapid(r) was found. However, only 2 patients with severe renal impairment were studied (<30 mL/min). Careful glucose monitoring and dose adjustments of insulin, including NovoRapid(r), may be necessary in patients with renal dysfunction. See WARNINGS AND PRECAUTIONS, Renal.

STORAGE AND STABILITY

Temperature:

NovoRapid(r) (insulin aspart) should be stored between 2 and 10EC (in a refrigerator) not near a freezing compartment. Do not freeze. Do not expose to excessive heat. Penfill(r) cartridges or vials in use or carried as a spare may be kept at ambient temperature (not above 30EC) for up to 4 weeks.

Light:

In order to protect from light, keep the cap on when NovoRapid(r) FlexPen(r) or NovoRapid(r) Penfill(r) in a Novo Nordisk Insulin Delivery Device is not in use. Keep out of sunlight.

Others:

NovoRapid(r)

DOSAGE FORMS, COMPOSITION AND PACKAGING

NovoRapid(r) (insulin aspart) is available in 10 ml vials (in cartons of 1 vial), in 3 ml Penfill(r) cartridges (in cartons of 5 cartridges), and in 3 ml NovoRapid(r) FlexPen(r) disposable pens (in cartons of 5 syringes). Each presentation is in a strength of 100 Units of insulin aspart per ml. The vials are made of Type 1 glass and are closed with a bromobutyl/polyisoprene rubber disc and a protective tamper-proof plastic cap.

NovoRapid(r) Penfill(r) cartridges are designed for use with Novo Nordisk Insulin Delivery Devices and NovoFine(r) needles as part of the All-In-One-System(r). NovoRapid(r) FlexPen(r) is specially designed for use with NovoFine(r) needles.

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Insulin Aspart Chemical name: B28 asp regular human insulin analogue Molecular formula and molecular mass: C256H381N65O79S6 and 5825.8 g/mole Insulin aspart is an analogue of human insulin, in which the amino acid proline in position B28 has been replaced by aspartic acid Structural formula of insulin aspart:

Physicochemical properties: Description: - white, or almost white, amorphous powder Solubilities:

Absorption: hygroscopic; will rapidly absorb significant quantities of moisture in humid environment 1 U (6 nmol = 1 unit) of insulin aspart is equimolar to 1 IU (international unit) of Human Insulin Standard.

Product Characteristics

The manufacture of the drug substance consists of the following three major steps: fermentation, recovery, and purification. In the recovery phase, the fermentation broth undergoes an alkaline treatment and the yeast cells are removed by centrifugation

CLINICAL TRIALS

Postprandial and overall glycemic control: In diabetic patients, NovoRapid(r) reduced postprandial blood glucose levels and improved the overall glycemic control by significantly reducing A1C as shown in two 6-month multicentre, randomized, parallel, open-label trials.21,22 Matabolic control, assessed by A1C was studied in 882 type 1 diabetic patients in one trial and 1065 type 1 diabetic patients in another trial, on a meal-related insulin regimen. With NovoRapid(r), significantly improved metabolic control was obtained compared to regular human insulin after 6 months treatment, the values being 7.78+-0.03% for NovoRapid(r) and 7.93+-0.05% (p <0.01) for regular human insulin in one trial and correspondingly 7.88+-0.03% and 8.00+-0.04% (p<0.02) in the other trial. This improvement in glycemic control with NovoRapid(r) was accompanied by a significant decrease of postprandial blood glucose levels after each meal, when compared to regular human insulin, without increasing the risk of hypoglycemic events Furthermore, NovoRapid(r) demonstrated a significant decrease in prandial blood glucose increments (defined as the mean difference between the blood glucose value 90 minutes after the meal and the blood glucose value just before the meal, over the 3 meals) when compared to regular human insulin; with values being -1.46mmol/L in one trial and -1.15 mmol/L in the other; p<00001).21,22 Data from an extension to one of these trials (n=598) showed that the effect of NovoRapid(r)on A1C was maintained for 3 years [value being 7.97 +- 0.11%] without increasing the risk of hypoglycemic events.23

Type 1 Diabetes:

Continuous subcutaneous insulin infusion (CSII) - Pump:

To evaluate the use of NovoRapid(r) by continuous subcutaneous insulin infusion (CSII) with an external pump, one open-label, randomized, parallel design study for 16 weeks [n=118]4 compared NovoRapid(r) versus Humalog(r) (insulin lispro) in patients with type 1 diabetes. Glycemic control (as measured by A1C) and rates of hypoglycemia were comparable. Patients with type 2 diabetes were also studied in an open-label, randomized, parallel design trial (24 weeks [n=127]. NovoRapid(r) by CSII was compared to a basal/bolus regimen of pre-prandial NovoRapid(r) and basal Novolin(r)ge NPH injections. Reductions in A1C and rates of hypoglycemia were comparable. In the study (NovoRapid(r) versus Humalog(r)), the rate of clogging or blockage events was similar between NovoRapid(r) and Humalog(r).

The safety and efficacy of an intensified insulin regimen with NovoRapid(r) was studied in an open-label study in 157 pregnant women with type 1 diabetes.33 Seventy two percent (113) were pregnant prior to entering the study (PBS) and 28% (44) entered the study before conception (PAS). The entry criteria for A1c were different between PBS and PAS (<8% vs. < 12%). PAS subjects were withdrawn if A!C was > 8% at conception, so in this subgroup only women who conceived and had A1c < 8% had efficacy and safety parameters evaluated. The proportions of patients reaching different A1C targets with NovoRapid(r) are presented in the following table. Summary of A1c (%) by Pregnancy status at Screening - ITT P

N: Number of subjects with a A1c measurement having the given value at the actual visit

%: Proportion of subjects with a A1c measurement having the given value at the actual visit Major and minor hypoglycemia rates for PBS and PAS by trimester are presented in the following table. All Treatment Emergent Hypoglycaemic Episodes During Pregnancy by Treatment, pregnancy status at Screening and trimester - ITT Pregnant

------------------------------------------------------------------------------------------------------------------------------------------------

All
Unclassifiable	Pregnant at Screening
	1. trimester	113	4	(3.5)	11	1.7
	2. trimester	113	9	(8.0)	58	1.8
	3. trimester	113	6	(5.3)	34	1.7

Pregnant after Screening
1. trimester	44	4	(9.1)	6	0.7
2. trimester	44	4	(9.1)	6	0.6
3. trimester	44	3	(6.8)	27	4.8

Rate: Number of Hypoglycaemic Episodes divided by years of exposure of subjects in the Population in the given trimester.

Type 2 Diabetes:

In patients with type 2 diabetes, a randomized, double-blind, multicentre, two period, cross-over study showed that 4-hour postprandial glucose excursion in 37 patients (BMI 27.05+-4.02, waist circumference 97.1+-11.7 cm) was 20% lower following a single injection of NovoRapid(r) (injected immediately before a meal test) than regular human insulin (injected 30 minutes before a meal test; p=0.034), independent of BMI. The insulin maximum concentration (Cmax) was significantly higher in patients receiving NovoRapid(r) (p=0.023) and was reached 27 minutes earlier (p=0.039), despite the fact that NovoRapid(r) was injected 30 minutes after human insulin.13 In 182 Type 2 diabetic patients treated with NovoRapid(r) in a meal-related regimen for 6 months, the pharmacodynamic properties of NovoRapid(r) were shown to be not different than regular human insulin with respect to metabolic control as assessed by insulin dose (meal related and NPH). Combination with long-acting basal insulin analog: In an open-label, parallel, randomized trial involving 595 patients with type 1diabetes, NovoRapid(r) in combination with insulin detemir significantly improved glycemic control when compared to regular human insulin with NPH insulin treatment. After 18 weeks of treatment, the mean A1C values were 7.88+- 0.05% vs 8.11+- 0.05% (95% CI; -0.34 to -0.10, p<0.001), respectively. In addition, the overall mean postprandial plasma glucose was significantly lower with the combination NovoRapid(r)/ detemir when compared to regular human insulin/ NPH (7.81 mmol/L vs 7.87 mmol/L, respectively; p<0.001) with significant less intra-individual variability in plasma glucose (p < 0.001). This improvement of glycemic control was accompanied with a significant decrease in the risk of nocturnal hypoglycemic events (relative risk decreased by 55%; 95% CI 0.35 - 0.58 ; p<0.001) and a significant decrease in body weight (p<0.001).14 Hypoglycemia: In a 16-week double-blind, randomized, multinational, crossover study with type 1 diabetes patients (n= 156, A1C <= 9.0%) the rate of major nocturnal hypoglycemic episodes was 72% lower with NovoRapid(r) than with regular human insulin {0.067 vs. 0.225 events/month, relative risk 0.28 (95% CI:0.13-0.59); p = 0.001)}. NPH insulin was given as basal insulin once or twice daily as needed. Furthermore, NovoRapid(r) significantly reduced the rate of minor hypoglycemic events when with the rate of minor events was significantly reduced by 7% with NovoRapid(r) compared to regular human insulin {2.98 vs 3.186 events/months, relative risk 0.93 (95% CI:0.87-1.00), p = 0.048}. While the total rate of major hypoglycemia did not differ significantly between treatments. Reductions in rate of hypoglycemia were achieved with NovoRapid(r) while maintaining overall glycemic control. The mean A1C remained constant, with values being 7.69% for NovoRapid(r) and 7.65% for regular human insulin (NS). Significant lower blood glucose values 90 minutes after breakfast (p=0.0001) and 90 minutes after dinner (p=0.023) were seen with NovoRapid(r) compared to regular human insulin. In another study (n=1065), significantly fewer patients (62% less) experienced major nocturnal hypoglycaemia with l NovoRapid(r) than with regular human insulin (1.3 vs 3.4% of patients, respectively; p<0.005).21

DETAILED PHARMACOLOGY

Animal Data

The biological activity of insulin aspart has been evaluated in vivo in mouse, rabbit and pig and,

In a comparison of hypoglycaemic activity of insulin aspart and human insulin in the diabetic ob/ob mouse, insulin aspart reduced moderate hyperglycemia to a similar extent as an equimolar dose of human insulin. The molar potency of insulin aspart was compared to that of a human insulin standard using the mouse blood glucose assay according to Ph. Eur. and the rabbit blood sugar method according to USP. Using the mouse blood glucose assay, the potency of three different batches of insulin aspart was determined to be 104.4% (95% confidence limits: 96.1-113.4%), 105.4% (93.8- 118.3%), and 104.8% (94.3-116.5%) relative to the first international human insulin standard. Thus, the potency of insulin aspart is not significantly different from that of human insulin in the mouse blood glucose assay. The molar potency of insulin aspart is defined as 1U = 6 nmol. Potency estimates for insulin aspart determined by the rabbit blood sugar assay were equivalent to those determined by the mouse blood glucose assay. Studies in pigs show that equimolar amounts of insulin aspart and human insulin have similar effects on blood glucose after i.v. administration, and that insulin aspart has a faster action than human insulin after s.c. administration. In the free fat cell bioassay, the potency of insulin aspart was determined to be 102.7 % (95% confidence limits: 99.6-105.8%) relative to a human insulin standard. Thus, the potency of insulin aspart is not significantly different from that of human insulin in free fat cells. The performed bioassays show that the potency of insulin aspart is equal to that of human insulin. Cardiovascular studies in anaesthetized rats and pigs plus a range of standard behavioural and organ function test and interaction studies have been conducted. Dose levels used in rodents were up to 100 times higher than the expected human therapeutic dose of 1 U/kg. In cats and pigs the high dose was 4 times higher than the expected human therapeutic dose due to the higher sensitivity of these species.

There was no significant difference in pharmacokinetics in a trial in Type 2 diabetic patients. No significant difference in efficacy, as assessed by A1C was found between genders in a trial in Type1 diabetic patients. There was no difference in efficacy in terms of blood glucose control as measured by A1C or safety in terms of adverse events between African Americans, Hispanics and Caucasian patients.

TOXICOLOGY

Acute Toxicity:

The results of the acute toxicity testing in rodents are dominated by reports of non-fatal convulsions and instances of ptosis, both attributed to hypoglycemia. The pattern of effects was that expected for an insulin given in high doses.

Long-term Toxicity:

Carcinogenicity:

Carcinogenicity trials have not been performed with NovoRapid(r) (insulin aspart). A series of repeated dose trials in animals (including 52 weeks dosing in rats and dogs) showed that none of the effects observed with NovoRapid(r) differed from those observed with regular human insulin. In vitro trials showed that the mitogenicity of NovoRapid(r) does not differ from that observed with regular human insulin. Animal trials on the mutagenic potential of NovoRapid(r) and regular human insulin did not show any difference between the two products.

Mutagenicity:

A comprehensive range of experiments have been completed and, insulin aspart gave negative results. Human insulin also gave negative results. It is concluded that insulin aspart is not a genotoxicant.

REFERENCES

Heinemann L., Weyer C., Rauhaus M., Heinrichs S., Heise T. Variability of the metabolic effect of s.c. injected regular insulin and the rapid acting insulin-analogue. B28-ASP. Diabetologia 1997; 40; A10. Round P.M., Olsen K.J., Home P.D. Improved blood glucose control with insulin analogue B28-ASP. Diabetologia 1996; 39; A24. Bode B W, Strange P. Efficacy, Safety and Pump Compatibility of Insulin Aspart Used in Continuous Subcutaneous Insulin Infusion Therapy in Patients with Type 1 Diabetes. Diabetes Care 2001; 24 (1); 69-72. Bode B, Raskin P, Weinstein R, Davidson J, Bell D, Henry R, McGill J, Huang WC, Nadeau D, Reinhardt R. Comparison of Insulin Aspart with Buffered Regular Insulin and Insulin Lispro in Continuous Subcutaneous Insulin Infusion A randomized study in type 1 diabetes. Diabetes Care 2002; 25 (3); 439-444.

merican Diabetes Association. Insulin Administration. Diabetes Care 1998; 21; S72-75.

Gittoes N.J.L., Kendall M.J., Ferner R.E. Drugs and diabetes mellitus. In: Pickup J., Williams G., eds. Textbook of Diabetes. Oxford, 1997; 69.1-69.12. Frier B.M. Hypoglycaemia in diabetes mellitus. In: Pickup J., Williams G., eds. Textbook of Diabetes. Oxford, 1997; 40.1-40.23. Amiel S.A. Insulin injection treatment and its complications. In: Pickup J., Williams G., eds. Textbook of Diabetes. Oxford, 1997; 33.1-33.20. Hanson U., Persson B., Enochsson E. Self-monitoring of blood glucose by diabetic women during the third trimester of pregnancy. Am. J. Obstet. Gynecol. 1985; 817-21.

eltzer s., Leiter L., Daneman D., Gerstein H.C., Lau D., Ludwig S., Yale J-F., Zinman B., Lillie D., Steering and Expert Committees. 1998 clinical practice guidelines for the management of diabetes in Canada. 1998; 159; S1-S29.

Duckworth WC. Insulin degradation: mechanisms, products, and significance. Endocrine Rev 1988; 9:319-344. Thomas JH et al. Int J Biochem 1983; 15:329-336.

Home PD, Lindholm A, Riis A. for the European Insulin Aspart Study Group. Insulin aspart vs human insulin in the management of long-term blood glucose control in type 1 diabetes mellitus: a randomized controlled trial. Diabetic Medicine 2000; 17: 762 - 770. Raskin P, Guthrie R., Leiter L., Riis A. Jovanovic L. Use of insulin aspart, a fast-acting insulin Analogue, as the mealtime insulin in the management of patients with type 1 diabetes. Diabetes Care 2000; 23(5): 583-588. Home PD, Hallgren , Usadel KH, Sane T, Faber J, Grill V, Friberg HH. Pre-meal insulin aspart compared with pre-meal soluble human insulin in type 1 diabetes. Diabetes Research and Clinical Practice 2006; 71:131-139 Heller SR, Colagiuri S, Vaaler S, Wolffenbuttel BHR., Keolendorf K, Friberg HH, Windfeld K, Lindholm A. Hypoglycemia with insulin aspart: a double-blind randomized, crossover trial in subjects with type 1 diabetes. Diabetic Medicine, 21, 769-775, 2004. Colagiuri S., Vaaler S.,. Wolffenbuttel B. H. R, Koelendorf K, Friberg H. H, Windfeld K., Lindholm A. Hypoglycaemia with insulin aspart: a double-blind, randomised, crossover trial in subjects with Type 1 diabetes. Diabetic Medicine 2004; 21:769-775 Danne T., Odendahl R., Naeke A., Schimmel U., Szczepanski R., Moeller J., Rastam J., Deiss Do. Postprandial insulin aspart is preferred to preprandial human insulin by parents of preschool children with type 1 diabetes. Diabetes 2005; 54(Suppl 1): A667 abstract. Arslanian S., Foster C., Wright N., Stender S., Hu P., Hale P., Hale D. Comparison of insulin aspart, regular insulin, and insulin lispro in basal bolus therapy with NPH to treat pediatric patients with type 1 diabetes mellitus Diabetes 2005; 54(Suppl 1):A517 abstract. Esposito K. Giugliano D, Napo F, Marfella R. Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus. Circulation 2004; 110:214- 219 Ceriello A. Postprandial hyperglycemia and diabetes complications. Is it time to treat?

Ceriello A. Impaired glucose tolerance and cardiovascular disease: The possible role of post- prandial hyperglycemia. Am Heart J 2004; 147:803-807 Holmes G., Galitz L., Hu P, Lyness W., Pharmacokinetics of insulin aspart in obesity, renal impairment, or hepatic impairment. Br J Clin Pharmacol 2005 In Press Hod, M, Damm, P, Kaaja R, et al. Fetal and perinatal outcomes in type 1 diabetes pregnancy: a randomized study comparing insulin aspart with human insulin in 322 subjects. American Journal of Obstetrics & Gynecology, 2007.

Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients
Subcutaneous Injection	solution for injection, 100 Units/mL	disodium phosphate dihydrate, glycerol, hydrochloric acid, metacresol, phenol, sodium chloride, sodium hydroxide 2N, zinc chloride solution, water for injection For a complete listing see Dosage Forms, Composition and Packaging section.

Number of subjects	113			44			157
	P	N	%	P	N	%	P	N	%
Visit P2 (week 12)
A 1c <= 6.0%	108	36	33.3	31	9	29.0	*	*	*
A 1c <= 6.5%	108	70	64.8	31	21	67.7	*	*	*
A 1c <= 7.0%	108	98	90.7	31	26	83.9	*	*	*
Visit P3 (week 24)
A 1c <= 6.0%	102	66	64.7	31	13	41.9	133	79	59.4
A 1c <= 6.5%	102	83	81.4	31	27	87.1	133	110	82.7
A 1c <= 7.0%	102	96	94.1	31	30	96.8	133	126	94.7
Visit P4 (week 36)
A 1c <= 6.0%	96	53	55.2	26	7	26.9	122	60	49.2
A 1c <= 6.5%	96	77	80.2	26	18	69.2	122	95	77.9
A 1c <= 7.0%	96	90	93.8	26	26	100.0	122	116	95.1
Follow-up Visit (6 weeks post partum)
A 1c <= 6.0%	104	35	33.7	36	8	22.2	140	43	30.7
A 1c <= 6.5%	104	58	55.8	36	20	55.6	140	78	55.7

1. trimester	157	137	(87.3)	1514	98.9
2. trimester	157	131	(83.4)	3664	85.7
3. trimester	157	112	(71.3)	2019	80.1

1. trimester	157	56	(35.7)	239	15.6
2. trimester	157	55	(35.0)	525	12.3
3. trimester	157	45	(28.7)	291	11.5

Test	Insulin Aspart/ Human Insulin(HI)	Results
Irwin Observation Test, mice	1,10 or 100 U/kg IV, HI 100 IU/kg IV	No difference from human insulin was observed
Locomotor Activity, rats	1,10 or 100 U/kg IV, HI 100 IU/kg IV	No consistent effect
Rotarod Performance, mice	1,10 or 100 U/kg IV, HI 100 IU/kg IV	No effects
Hexobarbital induced sleeping time, mice	1,10 or 100 U/kg i.v. HI 100 IU/kg IV	No difference from human insulin was observed
Ethanol induced sleeping time, mice	1,10 or 100 U/kg IV, HI 100 IU/kg IV	No difference from human insulin was observed
Anti-convulsant activity, mice	1,10 or 100 U/kg IV, HI 100 IU/kg IV	No effects
Pro-convulsant activity, mice	1,10 or 100 U/kg IV, HI 100 IU/kg IV	No effects
Analgesic effect on acetic acid induced writhing	1,10 or 100 U/kg IV, HI 100 IU/kg IV	No effects
Effects on body temperature	1,10 or 100 U/kg IV, HI 100 IU/kg IV	No effects
Isolated guinea-pig ileum	3.6, 36 or 360 mU/ml HI: 360 mIU/ml	No effects
Autonomic nervous system in anaesthetised cat	0.4, 1.0 and 4.0 U/kg IV, HI: 0.4, 1.0 and 4.0 IU/kg IV	No difference from human insulin was observed
Cardiovascular and Respiratory Systems in anaesthetised rat	1,10 and 100 U/kg IV, HI: 1,10 and 100 IU/kg IV	No effects
Cardiovascular and Respiratory Systems in anaesthetised pig	0.4, 1.0 and 4.0 U/kg IV. HI: 0.4, 1.0 and 4.0 IU/kg IV	No difference from human insulin was observed
Gastrointestinal Motility in Mice	1,10 or 100 U/kg IV, HI 100 IU/kg IV	No effects
Renal Function in	1,10 or 100 U/kg	No effects in general
Test	Insulin Aspart/ Human Insulin(HI)	Results
Rats	IV, HI 100 IU/kg IV

Major	Pregnant at Screening
	1. trimester	113	19	(16.8)	34	5.2
	2. trimester	113	22	(19.5)	44	1.3
	3. trimester	113	9	(8.0)	20	1.0

Pregnant after	Screening
1. trimester		44	5	(11.4)	7	0.8
2. trimester		44	5	(11.4)	7	0.7
3. trimester		44	1	(2.3)	1	0.2

1. trimester	157	24	(15.3)	41	2.7
2. trimester	157	27	(17.2)	51	1.2
3. trimester	157	10	(6.4)	21	0.8

Minor	Pregnant at Screening
	1. trimester	113	97	(85.8)	907	138.4
	2. trimester	113	98	(86.7)	2992	90.9
	3. trimester	113	85	(75.2)	1639	83.7

Symptoms only	Pregnant at Screening
	1. trimester	113	32	(28.3)	154	23.5
	2. trimester	113	40	(35.4)	407	12.4
	3. trimester	113	34	(30.1)	256	13.1

Species, Strain, Route	(M+F) Animals per group	Doses (U/kg)	Results
Mouse NMRI. SC	5 + 5	0, 62.5, 250, 1000, 4000	Highest non-lethal dose: 4000U/kg in males and 250U/kg in females.
Mouse, CD1, SC	5 + 5	0, 62.5, 250, 1000, 4000	Highest non-lethal dose: 4000U/kg
Mouse, NMRI, IV	5 + 5	0, 62.5, 250, 1000, 4000	Highest non-lethal dose: 4000U/kg in males and 1000 u/kg in females
Rat, S.D. SC	5 + 5	0, 62.5, 250, 1000, 4000	Highest non-lethal dose: 4000U/kg
Rat, S.D. SC	5 + 5	0, 62.5, 250, 1000, 2000.	Highest non-lethal dose: 2000Ukg
Rat, S.D. SC	5 + 5	0, 62.5, 250, 1000, 4000	Highest non-lethal dose: 4000U/kg
Rat, S.D. IV	5 + 5	0, 62.5, 250, 1000, 4000	Highest non-lethal dose: 4000 U/kg
Dog, Beagle, SC.	1 + 1	4, 8, 16, 32, 64 64 Old process	Highest non-lethal dose: 64U/kg Apart from hypoglycaemia no treatment-related signs or changes

Species	Strain	Number of groups and size	Dosing Method	Duration (Weeks)	Dose level (U/kg/day)	Results
Rat	Sprague- Dawley	5 Groups 10M, 10F/group, main 9M, 9F/group, satellites 5M, 5F in groups 1, 4 & 5 reversibility assessment	SC	4 weeks + 4 week recovery in groups 1, 4 & 5	0, 5, 25, 100 + 100	Hypoglycemia, increased food consumption and weight gain. No unexpected observations.
Rat	Sprague- Dawley	4 Groups 10M, 10F	SC	4 weeks	0, 12.5, 50, 200	Hypoglycemia. No unexpected observations.
Rat	Mol: WIST	4 Groups 15M, 15F	SC	13 weeks	0, 12.5, 50, 200	Hypoglycemia, increased weight gain. No unexpected observations.
Rat	Sprague- Dawley	4 Groups 32M, 32F Satellites included	SC	52 weeks	Top dose levels 100 bid for 24 weeks, 50 bid weeks 25-26, 100 od weeks 27-37, 75 od from week 38-52. Lower dose levels 5 and 25U/kg/bid for 26 weeks 10 and 50 od for 27-52 weeks. Controls.	Hypoglycemia, increased food and water consumption and weight gain. Excess of mammary tumours in high dose females.
Rat	Sprague- Dawley	4 Groups 20F	SC	52 weeks	200 per drug substance. Insulin aspart, human insulin, control.	Mammary tumour-incidence higher in insulin aspart group equal to human insulin both being higher than controls.
Dog	Beagle	4 groups 3M, 3F/group, main 1M, 1F in groups 1 & 4 reversibility assessment	SC	4weeks (+ 4 week recovery in groups 1 & 4)	0, 0.25, 0.5 , 1.0 bid	Hypoglycaemia. No unexpected observations.
Dog	Beagle	3 Groups 4M, 4F	SC	13 weeks	0,1, 4	Hypoglycaemia. No unexpected observations.
Dog	Beagle	4 Groups 4M, 4F	SC	52 weeks	0, 0.25, 0.5, 1.0 bid for 28 weeks same daily dose od from week 29- 52. HI- 1.0 bid 28 weeks 2.0 od from 29-52	Hypoglycaemia. No unexpected observations.

Pregnant after	Screening
1. trimester		44	40	(90.9)	607	69.3
2. trimester		44	33	(75.0)	672	68.1
3. trimester		44	27	(61.4)	380	67.4

Pregnant after	Screening
1. trimester		44	24	(54.5)	85	9.7
2. trimester		44	15	(34.1)	118	12.0
3. trimester		44	11	(25.0)	35	6.2