Data Sheet

LEVEMIR^®

Insulin detemir (rys) 100 Units/ml

Recombinant DNA origin: Saccharomyces cerevisiae

Presentation

Levemir is a sterile, clear, colourless, aqueous, neutral solution of insulin detemir human insulin analogue for subcutaneous injection. One unit of insulin detemir contains 0.142 mg salt-free anhydrous insulin detemir. One unit (U) of insulin detemir corresponds to one IU of human insulin. Levemir® is presented in 3 ml cartridges made of glass, closed with a rubber disc. The cartridges are included in Flexpen pre-filled syringes.

Uses

Actions

Pharmacotherapeutic group: Antidiabetic agent. Insulin and analogues, long- acting. ATC code: A10AE.

Levemir is a soluble, long-acting basal insulin analogue with a flat action profile with a prolonged duration of effect (Figure 1)

Figure 1: Activity profiles of Levemir in patients with type 1 diabetes.
*Data from Trial NN304-1338, a randomised, double-blind, cross-over trial involving 12 subjects.

The duration of action is up to 24 hours depending on dose. When administered twice daily, steady state serum concentrations are reached after 2 to 3 dose administrations. For doses of 0.2 to 0.4 U/kg, Levemir exerts more than 50% of its total pharmacodynamic effect within the approximate period of 3 - 14 hours after dose administration.

Dose proportionality in pharmacodynamic response (maximum effect, duration of action, total effect) is observed after subcutaneous administration.

The time action profile of Levemir is significantly less variable than NPH insulin and insulin glargine (Table 1).

Lower day-to-day variability in fasting plasma glucose (FPG) was demonstrated during treatment with Levemir compared to NPH in long-term clinical trials. The clinical benefit of this has not been demonstrated.

The prolonged action of Levemir is thought to be mediated by binding to plasma proteins, most likely albumin, via the fatty acyl side-chain. Insulin detemir is distributed more slowly to peripheral target tissues compared to isophane insulin.

The blood glucose lowering effect of Levemir is due to the facilitated uptake of glucose following binding of insulin detemir to receptors on muscle and fat cells and to decreased glucose output from the liver. In vitro testing of insulin detemir's binding to the insulin and IGF-1 receptors has shown that Levemir has reduced affinity to both receptors. The clinical correlates of this have not been established. The molar dose of insulin detemir is approximately fourfold higher compared with human insulin. One unit of Levemir is approximately equipotent to one international unit of human insulin.

Pharmacokinetics

Dose proportionality in serum concentrations (maximum concentration, extent of absorption) is observed after subcutaneous administration. When administered twice daily, steady state serum concentrations are reached after 2 to 3 dose administrations. The terminal half-life after subcutaneous administration is between 5 and 7 hours depending on dose. Maximum serum concentration is reached 6 to 8 hours after administration.

Intra-subject variation in absorption is lower for Levemir than for other basal insulin preparations. There was no clinically relevant difference between males and females in pharmacokinetic parameters of Levemir. The pharmacokinetic properties of Levemir were investigated in children (6-12 years) and adolescents (13-17 years) with type 1 diabetes, and compared to adults with type 1 diabetes. A total of 16 males and 18 females was studied. No difference in pharmacokinetics was observed between the three age groups. There was no clinically relevant difference in pharmacokinetics of Levemir between elderly and young subjects, or between subjects with renal or hepatic impairment and healthy subjects.

A small apparent volume of distribution for Levemir (approximately 0.1 L/kg) indicates that a high fraction of insulin detemir is circulating in the blood. The metabolism of insulin detemir is similar to that of human insulin.

The results of the in vitro and in vivo protein binding studies demonstrate that there is no clinically relevant interaction between Levemir and fatty acids or other protein bound drugs.

Indications

Treatment of diabetes mellitus where used as basal insulin in combination with meal-related short- or rapid-acting insulin. Not recommended for diabetes mellitus type 2 patients who still respond to oral hypoglycaemic agents. (See Clinical Trials.)

Dosage and Administration

Levemir is a long-acting insulin analogue used as basal insulin in combination with meal-related short- or rapid-acting insulin. The blood glucose lowering effect of Levemir has been demonstrated in clinical trials outside a basal bolus regimen.

The dosage of Levemir should be adjusted individually. Levemir should be administered once or twice daily depending on patients' needs. For patients who require twice daily dosing to optimise blood glucose control, the evening dose can be administered either with the evening meal, at bedtime, or 12 hours after the morning dose.

As with all insulins, in elderly patients and patients with renal or hepatic impairment, glucose monitoring should be intensified and insulin detemir dosage adjusted on an individual basis.

Adjustment of dosage may also be necessary if patients undertake increased physical activity, change their usual diet or during concomitant illness.

Levemir is administered subcutaneously by injection in the thigh, abdominal wall, the upper arm, or the gluteal region. As with human insulin, the rate and extent of absorption of insulin detemir may be higher when administered s.c. in the abdomen or upper arm as opposed to the thigh. Injection sites should be rotated within the same region. Formal studies with administration in the gluteal region have not been conducted.

Diabetes mellitus type 2

The role of Levemir in the treatment of diabetes mellitus type 2 has not been established. Outside a basal bolus regimen, non-inferiority of HbA_1c compared to NPH has not been demonstrated. Not recommended for diabetes mellitus type 2 patients who still respond to oral hypoglycaemic agents (see Clinical Trials).

Paediatric

No evaluated paediatric efficacy and safety data are available to support paediatric dosing advice.

Transfer from other insulins

Transfer to Levemir from intermediate or long-acting insulins may require adjustment of dose and timing of administration. As with all insulins, close glucose monitoring is recommended during the transition and in the initial weeks thereafter

Concomitant antidiabetic treatment may need to be adjusted (dose and timing of concurrent short-acting insulins or the dose of oral antidiabetic agents). An increase in soluble insulin requirements has been demonstrated in some individuals who have been transferred from human insulin to Levemir.

Contraindications

Hypersensitivity to insulin detemir or any of the excipients

Warnings and Precautions

Inadequate dosing or discontinuation of treatment, especially in type 1 diabetes, may lead to hyperglycaemia and diabetic ketoacidosis. Usually the first symptoms of hyperglycaemia develop gradually over a period of hours or days. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, loss of appetite as well as acetone odour of breath. In type 1 diabetes, untreated hyperglycaemic events eventually lead to diabetic ketoacidosis, which is potentially lethal.

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement (see 'Adverse Effects' and 'Overdosage').

Omission of a meal or unplanned strenuous physical exercise may lead to hypoglycaemia.

Patients whose blood glucose control is greatly improved, for example by intensified insulin therapy, may experience a change in their usual warning symptoms of hypoglycaemia, and should be advised accordingly. Usual warning symptoms may disappear in patients with longstanding diabetes.

Concomitant illness, especially infections and feverish conditions, usually increases the patient's insulin requirements.

Intramuscular administration should be avoided. Levemir is not to be administered intravenously as it may result in severe hypoglycaemia.

If Levemir is mixed with other insulin preparations the profile of action of one or both individual components may change. Mixing Levemir with a rapid-acting insulin analogue like insulin aspart will reduce and delay the maximum effect of the rapid-acting insulin compared to that observed following separate injections.

Insulin detemir is not to be used in insulin infusion pumps.

No studies have been performed in children under the age of 6 years.

Transfer of patients between insulin types

Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type, origin (animal, human, human insulin analogue) and/or method of manufacture (recombinant DNA versus animal source insulin) may result in the need for a change in dosage. Patients taking Levemir may require a change in dosage from that used with their usual insulin. If an adjustment is needed, it may occur with the first dose or during the first few weeks or months.

Carcinogenicity, Mutagenicity and Impairment of Fertility

The carcinogenic potential of insulin detemir has not been investigated in long-term animal studies. Insulin detemir was not genotoxic in assays for reverse gene mutation in bacterial or chromosomal damage in cultured human lymphocytes. An in vivo micronucleus test in mice was also negative. No adverse effects on male or female fertility were apparent in a study in rats dosed at levels up to 50 U/kg/day SC.

Use in Pregnancy

Pregnancy Category: B3

There is no clinical experience with insulin detemir during pregnancy.

Animal reproduction studies showed increases in post-implantation loss and fetal anomalies in rats following treatment with insulin detemir at doses of 25-50 U/kg/day SC. A teratology study in rabbits revealed increased in utero deaths and post-implantation losses following dosing with 37.5 U/kg/day SC. Lower doses were not tested. Similar effects have also been reported for human insulin and other human insulin analogues. These effects are probably secondary to maternal hypoglycaemia.

In general, intensified blood glucose control and monitoring of pregnant women with diabetes are recommended throughout pregnancy and when contemplating pregnancy. Insulin requirements usually fall in the first trimester and increase subsequently during the second and third trimester. After delivery, insulin requirements normally return rapidly to pre-pregnancy values.

Use in lactation

There is currently no clinical experience with insulin detemir during lactation. Lactating women may require adjustments in insulin dose and diet.

Effects on ability to drive and use machines

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

Patients should be advised to take precautions to avoid hypoglycaemia while driving. This is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.

Adverse Effects

Clinical trial data

Levemir has been administered to a total of 3159 subjects in all clinical trials, including 2446 patients in the intermediate and long term trials (4 - 12 months).

Table 3: Comparative incidence of adverse events (% of patients) during intermediate and long term clinical trials

Treatment emergent adverse events; Levemir incidence = 1.0 % and > isophane human insulin group.

*N = number of patients exposed to each treatment arm

Other treatment emergent adverse events reported in association with Levemir with incidences greater than or equal to 1.0 % in the intermediate and long-term trials were:

Metabolic and nutritional disorders:  Minor hypoglycaemia, major hypoglycaemia, hyperglycaemia

Respiratory system disorders:  Coughing, pneumonia, sinusitis

Gastrointestinal disorders:  Diarrhoea, nausea, tooth ache, dyspepsia

Vision disorders:  Retinal disorder, conjunctivitis

Musculo-skeletal system disorders:  Skeletal pain, myalgia, arthralgia

Resistance mechanism disorders:  Viral infection

Psychiatric disorders:  Anxiety

Reproductive disorders, female:  Dysmenorrhoea

The most common overall adverse drug reaction reported in clinical trials with Levemir was hypoglycaemia. Such reactions following treatment with Levemir were mostly mild and easily handled. Symptoms of hypoglycaemia usually occur suddenly. They may include cold sweats, 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 hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death.

Oedema and refraction anomalies may occur upon initiation of insulin therapy. These symptoms are usually transitory in nature.

Local hypersensitivity reactions (redness, swelling and itching at the injection site) may occur during treatment with insulin. These reactions are usually transitory and normally disappear with continued treatment.

Generalised hypersensitivity reactions may rarely occur. Such reactions are potentially life-threatening.

Lipodystrophy may occur at the injection site as a consequence of failure to regularly change the site of injection.

Interactions

Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia (see 'Adverse Effects' and 'Overdosage').

A number of medicinal products are known to interact with glucose metabolism. Possible interactions must therefore be taken into account by the physician.

The following substances may reduce the patient's insulin requirements:

Oral hypoglycaemic agents (OHAs), octreotide, lanreotide, monoamine oxidase inhibitors (MAOIs), non-selective beta-adrenergic blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates, alcohol, anabolic steroids (except danazol and oxymetholone), alpha-adrenergic blocking agents, quinine, quinidine and sulphonamides.

The following substances may increase the patient's insulin requirements:

Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, octreotide, lanreotide, growth hormone, diazoxide, asparaginase, nicotinic acid, oxymetholone and danazol.

Insulin detemir is greater than 97% protein-bound in plasma, independent of gender. The results of in vitro studies do not suggest any clinically relevant albumin binding interactions between insulin detemir and fatty acids or other protein-bounds drugs (such as warfarin, frusemide, tolbutamide, diazepam, glibenclamide, nicardipine, repaglinide, aspirin or valproic acid) or other drugs known to bind to domains IIA and IIIA of the albumin molecule. As there is a vast excess (about 400 000) of albumin binding sites available in plasma per insulin detemir molecule, there would be little risk that lower albumin concentrations resulting from some disease states like nephrotic syndrome might affect the ratio of bound to free insulin detemir or that acute displacement could occur. This is supported by in vitro studies as well as subgroup analyses from the clinical trial programme.

Beta blockers may mask the symptoms of hypoglycaemia and delay recovery from hypoglycaemia.

Alcohol may intensify and prolong the hypoglycaemic effect of insulin.

Overdosage

Insulins have no specific overdose definitions. However, hypoglycaemia may develop over sequential stages:

• Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is therefore recommended that the diabetic patient always carry some sugary food or drink with them, for example, a few biscuits.
• Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated by glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, or by 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 oral carbohydrates is recommended for the patient in order to prevent a relapse.

Pharmaceutical Precautions

Instructions for use and handling

Levemir FlexPen^® is for use by one person only. Levemir FlexPen must not be used if they have been frozen, and must not be used unless the insulin appears clear and colourless.

The carton contains a Consumer Medicine Information package leaflet with instructions for use and handling.

The cartridge inside Levemir FlexPen must not be refilled. NovoFine short cap needles are designed to be used with Levemir FlexPen. The patient should be advised to discard the needle after each injection.

Incompatibilities

Substances added to Levemir may cause degradation of insulin detemir, for example if the medicinal product contains thiols or sulphites. Levemir should not be added to infusion fluids.

Shelf-life

The in-use time is 4 weeks.

Special precautions for storage

Levemir FlexPen should be stored between 2°C and 8°C. Do not freeze.

The in-use time is 4 weeks.

Levemir products in use or carried as spares should be kept at ambient temperature (at or below 30°C) for up to 4 weeks, but any remainder must then be discarded. They should not be exposed to excessive heat or sunlight.

Medicine Classification

Prescription Medicine

Package Quantities

Levemir contains insulin detemir 100 U/mL.

Levemir^® FlexPen^®

Levemir FlexPen is a pre-filled, multidose, disposable syringe consisting of a pen injector and a 3mL cartridge. The cartridge is made of glass, contains a bromobutyl rubber piston and is closed with a latex-free bromobutyl/polyisoprene rubber disc. The pen injector is made of plastic (polypropylene, POM). Five Levemir FlexPen are packed in a carton.

Further Information

Clinical Trials

The confirmatory therapeutic clinical development programme to evaluate the efficacy and safety of insulin detemir consisted of ten phase 3, randomised, parallel-group (versus isophane insulin), open-label, multicentre clinical trials. The trial programme randomised a total of 1945 adult patients with type 1 diabetes and a total of 871 patients with type 2 diabetes. Five of the studies employed the marketed formulation, and the remaining five employed a less concentrated (but nevertheless bioequivalent) 'early-development' formulation.

The results of an on-going efficacy study in paediatric patients have not been reviewed at the present time.

In intermediate and long-term treatment trials intended to demonstrate the non-inferiority of the marketed formulation of Levemir to human insulin, the primary outcome was HbA_1c. Secondary outcomes included FPG levels, 9 or 10 point blood glucose profiles, within-subject variation for fasting blood glucose (FBG), hypoglycaemia, quality of life, antibody levels, daily doses and safety profiles as measured by adverse events, laboratory safety parameters, physical examination, weight and vital signs.

Levemir provides equivalent glycaemic control as measured by HbA_1c and better glycaemic control as measured by FPG, although not at some other times as determined by 9 point blood glucose profiles, compared to human isophane insulin treatment in type 1 diabetes. Intensive therapy with Levemir is also associated with lower day-to-day FBG variation and equivalent safety profiles except for weight. Levemir is not associated with weight gain over 4 - 6 months in type 1 diabetes, however the trials were not designed to test for this outcome and the clinical benefit of this has not been demonstrated.

Clinical studies in type 1 diabetes

In three large randomised, controlled clinical studies, adult patients with type 1 diabetes (1335 study, N = 749; 1447 study, N = 400; 1448 study, N = 409) were randomised to basal/bolus treatment with once- or twice-daily Levemir (marketed formulation insulin detemir) or with NPH insulin once- or twice-daily, for 4 to 6 months. The bolus (mealtime) treatment was soluble human insulin (1335 study) or insulin aspart (1447 and 1448 studies). In these studies, Levemir and NPH had a similar effect on the primary outcome of HbA_1c (Table 2). In the secondary outcomes, Levemir demonstrated significantly improved FPG (Table 2) and within-subject variation (1335 study p<0.001, 1447 study p<0.001; 1448 study p<0.001), with similar overall rates of hypoglycaemia and safety profiles including adverse events, laboratory safety parameters, physical examination, and vital signs, compared with NPH insulin. In a 9 point blood glucose profile (1335 study), the overall profiles were significantly different between Levemir and NPH insulin (p=0.006), with blood glucose concentrations being lower from before breakfast and throughout the day until after bedtime, in the Levemir group. In 10 point blood glucose profiles (1447 and 1448 studies), the overall profiles were similar during the day but tended to differ at night, with lower night-time blood glucose concentrations in some of the Levemir groups. In the 1335 study, antibody formation was increased with Levemir but did not compromise glycaemic control.

Table 2. Results in type 1 diabetes

^#N = number of patients randomised. ^§Marketed formulation insulin detemir. *Once daily NPH insulin may be expected to favour Levemir. ⁸Data from both arms pooled. Baseline values were included as covariates in an ANOVA analysis.

Two additional multicentre, open-label, randomised, confirmatory clinical trials were conducted in type 1 diabetes to assess HbA_1c response during treatment for up to 6 months. Twice-daily Levemir (early-development formulation insulin detemir) or NPH insulin were compared when combined with bolus insulin aspart (1205 study; N = 448) or with bolus soluble human insulin (1181 study; N = 461). At the end of 6 months of treatment, the primary outcomes of mean HbA_1c values were equivalent for Levemir and NPH in both studies. In the 1205 study, the secondary outcomes which were statistically different between treatment groups included lower within-subject variation in FBG with Levemir compared with NPH insulin (p<0.001), lower relative risk (0.78) of hypoglycaemia with Levemir compared with NPH insulin [95%CI: 0.62, 0.97], and a significant difference in the 9 point blood glucose profile, with blood glucose concentrations lower before breakfast and higher from lunch through 02:00 hours in the Levemir group compared with the NPH insulin group (p=0.036). The mean doses of both basal and bolus insulins were higher after 6 months in the Levemir group compared with the NPH group.

Both 1205 and 1181 clinical trials were extended for an additional 6 months (as trial IDs 1316 and 1243 respectively) to assess maintenance of Levemir efficacy up to a period of 1 year of treatment. At the end of extension trials 1316 and 1243, HbA_1c values for Levemir treatment were equivalent to those of the NPH parallel treatment group.

Clinical studies in type 2 diabetes

Basal/bolus therapy (study 1336)

Study 1336 (N = 505) was a 6 month, phase 3, multicentre, open, randomised, parallel study of Levemir (marketed formulation insulin detemir) and NPH in patients with type 2 diabetes treated with a basal/bolus regimen. Insulin aspart was employed as the bolus insulin. The primary endpoint was HbA_1c, and after 6 months the reduction in HbA_1c was non-inferior for insulin detemir versus NPH (mean difference (insulin detemir - NPH) [95% CI] was 0.157 [0.003, 0.312]). Secondary endpoints such as FPG, 9 point blood glucose profiles, hypoglycaemia (total and nocturnal), quality of life and most of the safety profiles were all similar between the two treatment groups. The within-subject variation in FBG (p=0.021) was significantly lower for Levemir compared with NPH insulin.

Results of other ongoing studies supporting the basal/bolus use of Levemir in patients with type 2 diabetes mellitus are not yet available.

Combination therapy with metformin (study 1337)

Study 1337 (N = 467, of whom 405 completed the study) was a 6 month, phase 3, multicentre, open, randomised, parallel study of combination metformin with once daily evening Levemir (marketed formulation insulin detemir) or NPH in patients with type 2 diabetes previously inadequately controlled with monotherapy or oral combination therapy of metformin. The primary endpoint was HbA_1c and after 6 months, Levemir was inferior to NPH insulin according to the primary study outcome variable (mean difference (insulin detemir - NPH) [95% CI] was 0.56 [0.33, 0.78]). An absolute reduction in HbA_1c of approximately 1% from baseline was demonstrated with Levemir plus metformin. Secondary endpoints included FPG, 9 point blood glucose profiles, within-subject variability, hypoglycaemia and safety profiles. Levemir had equivalent FPG and within-subject variability compared to NPH treatment, and inferior 9 point blood glucose profile after 6 months. Compared with NPH, Levemir was associated with significantly fewer episodes of total hypoglycaemia, including all sub-categories of hypoglycaemia, but these results must be understood in light of the failure to demonstrate non-inferiority in terms of the primary efficacy endpoint, HbA_1c.

Basal monotherapy (study 1166)

Study 1166 (N = 439) was a 6 month, phase 3 basal monotherapy study of twice-daily Levemir (early-development formulation insulin detemir) versus NPH, in patients aged 35 years or more with type 2 diabetes receiving = 120 IU total insulin per day. The primary endpoint was HbA_1c, and after 6 months Levemir was inferior to NPH insulin (mean difference (insulin detemir - NPH) [95% CI] was 0.660 [0.436, 0.885]). Secondary endpoints included FPG, 9 point blood glucose profiles, within-subject variability, hypoglycaemia and weight control. FPG and 9 point blood glucose profiles were inferior with Levemir compared with NPH. Within-subject variability and hypoglycaemia were similar between the two treatment arms. Withdrawals due to lack of efficacy were seen in 10.7% of Levemir subjects versus 0.7% of NPH subjects.

List of excipients

Mannitol
Phenol
Metacresol
Zinc acetate
Dibasic sodium phosphate dihydrate
Sodium chloride
Hydrochloric acid
Sodium hydroxide
Water for injections

Trademarks

Levemir, FlexPen and NovoFine are registered trademarks owned by Novo Nordisk A/S

Name and Address

Novo Nordisk Pharmaceuticals Ltd.
PO Box 51-268
Pakuranga
Auckland

Tel: (09) 916 5590

Fax: (09) 916 5595

Date of Preparation

2 May 2005

Version 2