Levemir

Levemir

insulin detemir

Manufacturer:

Novo Nordisk

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Insulin detemir.
Description
Levemir contains insulin detemir (produced by recombinant DNA technology in Saccharomyces cerevisiae). It also contains the following excipients: Glycerol, phenol, metacresol, zinc acetate, disodium phosphate dihydrate, sodium chloride, hydrochloric acid, sodium hydroxide and water for injections.
One unit of insulin detemir contains 0.142 mg salt-free anhydrous insulin detemir. One unit (u) of insulin detemir corresponds to 1 iu of human insulin.
Action
Pharmacotherapeutic Group: Antidiabetic agent. Insulin and analogues, long-acting for injection. ATC Code: A10AE05.
Pharmacology: Pharmacodynamics: Insulin detemir is a soluble, long-acting basal insulin analogue with a flat action profile with a prolonged duration of effect.
The time action profile of insulin detemir is significantly less variable than for NPH insulin and insulin glargine in Type 1 diabetes subjects. (See Table 1.)

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The prolonged action of insulin detemir is mediated by the strong self-association of insulin detemir molecules at the injection site and albumin binding via the fatty acid side-chain. Insulin detemir is distributed more slowly to peripheral target tissues compared to NPH insulin. These combined mechanisms of protraction provide a more reproducible absorption and action profile of insulin detemir compared to NPH insulin. The blood glucose lowering effect of insulin detemir is due to the facilitated uptake of glucose following binding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucose output from the liver.
The duration of action is up to 24 hrs depending on dose providing an opportunity for once or twice-daily administration. If administered twice daily, steady state will occur after 2-3 dose administrations. For doses in the interval of 0.2-0.4 u/kg, Levemir exerts >50% of its maximum effect from 3-4 hrs and up to approximately 14 hrs after dose administration. Dose proportionality in pharmacodynamic response (maximum effect, duration of action, total effect) is observed after SC administration.
Lower day-to-day variability in FPG was demonstrated during treatment with Levemir compared to NPH in long-term clinical trials.
Studies in patient with type 2 diabetes treat with basal insulin combination with oral antidiabetic drugs demonstrated that glycaemic control (HBA10) with Levemir is comparable to NPH insulin and insulin glargine and associated with less weight gain, see Table 2. In the study versus insulin glargine, insulin detemir was allowed to be administered once or twice daily whereas insulin glargine was to be administered once a day, 55% of the insulin detemir-treated subjects completed the 52 weeks of treatment on the twice daily regimen. (See Table 2.)

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In trials with the use of OAD-insulin combination therapy Levemir treatment resulted in a 61-65% lower risk of minor nocturnal hypoglycaemia compared to NPH insulin.
In long-term treatment trials in patients with type 1 diabetes, fasting plasma glucose was improved with Levemir compared with NPH insulin when given as basal/bolus therapy including in children and adolescents aged 6-17. Glycaemic control (HbA1c) with Levemir is comparable to NPH insulin, with a lower risk of norturnal hypoglycaemia and no associated weight gain.
Antibody development has been observed with the use of Levemir. However, this does not appear to have any impact on glycaemic control.
Pharmacokinetics: Absorption: Maximum serum concentration is reached between 6 and 8 hrs after administration. When administered twice daily, steady state serum concentrations are reached after 2-3 dose administrations.
Intra-subject variation in absorption is lower for Levemir than for other basal insulin preparations.
There are no clinically relevant differences between genders in pharmacokinetic properties of insulin detemir. The absolute bioavailability of insulin detemir when administered SC is approximately 60%.
Distribution: An apparent volume of distribution for insulin detemir (approximately 0.1 L/kg) indicates that a high fraction of insulin detemir is circulating in the blood.
Metabolism: Degradation of insulin detemir is similar to that of human insulin; all metabolites formed are inactive. The results of the in vitro and in vivo protein-binding studies suggest that there is no clinically relevant interaction between insulin detemir and fatty acids or other protein-bound drugs.
Elimination: The terminal t½ after SC administration is determined by the rate of absorption from the subcutaneous tissue. The terminal t½ is between 5 and 7 hrs depending on dose.
Linearity: Dose proportionality in serum concentrations (maximum concentration, extent of absorption) is observed after SC administration in the therapeutic dose range.
Special Populations: The pharmacokinetic properties of insulin detemir were investigated in children (6-12 years) and adolescents (13-17 years) and compared to adults with type 1 diabetes. There was no clinically relevant difference in pharmacokinetic properties.
There was no clinically relevant difference in pharmacokinetics of insulin detemir between elderly and young subjects or between subjects with renal or hepatic impairment and healthy subjects. No clinically relevant differences in the pharmacokinetics of insulin detemir are expected between healthy subjects and subjects with renal or hepatic impairment, based on the studies performed. As the pharmacokinetics of insulin detemir has not been studied extensively in these populations, it is advised to monitor plasma glucose closely in these populations.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction. Receptor affinity data and in vitro mitogenicity tests revealed no evidence of an increased mitogenic potential compared to human insulin.
Indications/Uses
Treatment of diabetes mellitus.
Dosage/Direction for Use
Dosage: In combination with oral antidiabetic agents it is recommended to initiate Levemir treatment with once daily administration at a dose of 10 u or 0.1-0.2 u/kg.
The dose of Levemir should be titrated based on individual patients' needs.
Based on study results, the following titration guideline is recommended (see Table 3).

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When Levemir is used as part of a basal-bolus insulin regimen 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 with the evening at bedtime or 12 hrs after the morning dose.
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.
The efficacy and safety of Levemir have not been studied in children <6 years. Levemir has been studied in children and adolescents aged 6-17 years old with Type 1 diabetes (see Pharmacodynamics under Actions).
Concomitant antidiabetic treatment may need to be adjusted (dose and timing of concurrent short-acting insulins or the dose of oral antidiabetic agents).
Dosage Adjustment: 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.
Administration: Levemir is administered SC by injection in the thigh, abdominal wall or upper arm. As with human insulins, the rate and extent of absorption of insulin detemir may be higher when administered SC in the abdomen or upper arm than in the thigh. Injection sites should be alternated within the same region.
Instructions to be Given to the Patient on How to Handle Levemir FlexPen: Levemir FlexPen is a unique dial-a-dose insulin pen. Doses from 1-60 units in increments of 1 unit can be dialed. Levemir FlexPen is especially designed to be used with NovoFine S needles of 8 mm or shorter in length. Look for an S on the needle box. The S stands for short cap. Levemir FlexPen is for single person use only. Do not use it if it has not been stored correctly. As a precautionary measure the patient should always carry a spare insulin delivery device in case FlexPen is lost or damaged.
Getting Started: Check the label to be sure that Levemir FlexPen contains the correct type of insulin. Take off the pen cap. Disinfect the rubber membrane with a medicinal swap. Always use a new needle for each injection to prevent contamination. Remove the protective tab from a NovoFine S short cap needle. Screw the needle straight and tightly onto Levemir FlexPen. Pull off the big outer needle cap and the inner needle cap. Do not discard the big outer needle cap.
Priming to Expel Air Prior to Each Injection: Small amounts of air may collect in the needle and cartridge during normal use.
To avoid injection of air and ensure proper dosing: Dial 2 units. Hold Levemir FlexPen with the needle pointing upwards and tap the cartridge gently with a finger a few times to make any air bubbles collect at the top of the cartridge. Keeping the needle upwards, press the push-button all the way in. The dose selector returns to zero. A drop of insulin should appear at the needle tip. If not, repeat the procedure no more than 6 times.
If a drop of insulin still does not appear, the device is defective, and must not be used.
Setting the Dose: Check that the dose selector is set at zero. Dial the number of units needed to inject. The dose can be corrected either up or down by turning the dose selector in either direction. When dialing back, be careful not to push the push-button as insulin will come out. Do not use the residual scale to measure the dose of insulin. A dose larger than the number of units left in the cartridge cannot be set.
Making the Injection: Insert the needle into the skin. Deliver the dose by pressing the push-button all the way in. Be careful only to push the push-button when injecting. Keep the push-button fully depressed after the injection until the needle has been withdrawn from the skin. The needle should remain under the skin for at least 6 sec. This will ensure that the full dose has been delivered.
Removing the Needle: Replace the big outer needle cap and unscrew the needle. Dispose of it carefully. Use a new needle for each injection. Be sure to remove the needle and discard the needle after each injection and store Levemir FlexPen without the needle attached. Otherwise, the liquid may leak out which can cause inaccurate dosing. Healthcare professionals, relatives and other carers should follow general precautionary measures for removal and disposal of needles to eliminate the risk of unintended needle penetration. Dispose of the used Levemir FlexPen carefully without the needle attached.
Maintenance: Levemir FlexPen is designed to work accurately and safely. It should be handled with care. If it is dropped, or crushed, there is a risk of damage and leakage of insulin. Do not refill Levemir FlexPen. Clean the exterior of Levemir FlexPen by wiping it with a medicinal swap. Do not soak it in surgical spirit or wash or lubricate it. This may damage the mechanism.
Overdosage
A specific overdose for insulin cannot be defined, however, hypoglycaemia may develop over sequential stages if too high doses relative to the patient's requirement are administered: Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is therefore recommended that the diabetic patient always carry sugar containing products.
Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated by glucagon (0.5-1 mg) given IM or SC by a trained person, or by glucose given IV by a medical professional. Glucose must also be given IV, if the patient does not respond to glucagon within 10-15 mins. Upon regaining consciousness, administration of oral carbohydrates is recommended for the patient in order to prevent a relapse.
Contraindications
Hypersensitivity to insulin detemir or to any of the excipients.
Special 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.
Omission of a meal or unplanned strenuous physical exercise may lead to hypoglycaemia.
Patients, whose blood glucose control is greatly improved eg, 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 requirement.
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 1st dose or during the first few weeks or months.
As with any insulin therapy, injection site reactions may occur and include pain, itching, hives, sweling and inflammation. Continuous rotation of the injection site within a given area may help to reduce or prevent these reactions. Reactions usually resolve in a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of Levemir.
Levemir should not be administered IV as it may result in severe hypoglycaemia. IM administration should be avoided.
If Levemir is mixed with other insulin preparations, the profile of action of one or both individual components will change. Mixing Levemir with a rapid-acting insulin analogue eg, insulin aspart, results in an action profile with a lower and delayed maximum effect compared to separate injections. Therefore, mixing of rapid-acting insulin with Levemir should be avoided.
There are limited data in patients with severe hypoalbuminaemia. Careful monitoring is recommended in these patients.
Levemir is not to be used in insulin infusion pumps.
Levemir contains metacresol, which may cause allergic reactions.
Effects on the Ability to Drive or Operate Machinery: 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 (eg, 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.
Use in pregnancy & lactation: There is no clinical experience with insulin detemir during pregnancy or lactation. Caution should be exercised when prescribing to pregnant and lactating women.
Animal reproduction studies have not revealed any differences between insulin detemir and human insulin regarding embryotoxicity and teratogenicity.
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 1st trimester and increase subsequently during the 2nd and 3rd trimester. After delivery, insulin requirements normally return rapidly to pre-pregnancy values.
Lactating women may require adjustments in insulin dose and diet.
Use In Pregnancy & Lactation
There is no clinical experience with insulin detemir during pregnancy or lactation. Caution should be exercised when prescribing to pregnant and lactating women.
Animal reproduction studies have not revealed any differences between insulin detemir and human insulin regarding embryotoxicity and teratogenicity.
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 1st trimester and increase subsequently during the 2nd and 3rd trimester. After delivery, insulin requirements normally return rapidly to pre-pregnancy values.
Lactating women may require adjustments in insulin dose and diet.
Adverse Reactions
Adverse drug reactions observed in patients using Levemir are mainly dose-dependent and due to the pharmacologic effect of insulin. Hypoglycaemia is a common undesirable effect. It may occur if the insulin dose is too high in relation to the insulin requirement. From clinical investigations, it is known that major hypoglycaemia, defined as requirement for third party intervention, occurs in approximately 6% of the patients treated with Levemir. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death.
Injection site reactions are seen more frequently during treatment with Levemir than with human insulin. These reactions include redness, inflammation, swelling and itching at the injection site. Most of the injection site reactions are minor and of a transitory nature ie, they normally disappear during continued treatment in a few days to a few weeks. The overall percentage of treated patients expected to experience adverse drug reactions is estimated to be 12%.
Frequencies of adverse drug reactions from clinical trials, which by an overall judgment are considered related to Levemir are listed as follows.
Metabolism and Nutrition Disorders: Common (>1/100, <1/10): Hypoglycaemia: Symptoms of hypoglycaemia usually occur suddenly. They may include cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiousness, 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.
General Disorders and Administration Site Conditions: Common (>1/100, <1/10): Injection Site Reactions: Injection site 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.
Uncommon (>1/1000, <1/100): Lipodystrophy: Lipodystrophy may occur at the injection site as a consequence of failure to rotate injection sites within an area.
Oedema: Oedema may occur upon initiation of insulin therapy. These symptoms are usually of transitory nature.
Immune System Disorders: Uncommon (>1/1000, <1/100): Allergic Reactions, potentially allergic reactions, Urticaria, Rash and Eruptions: Such symptoms may be due to generalised hypersensitivity. Other signs of generalised hypersensitivity may be itching, sweating, gastrointestinal upset, angioneurotic oedema, difficulties in breathing, palpitation and reduction in blood pressure. Generalised hypersensitivity reactions are potentially life threatening (anaphylactic reactions).
Eye Disorders: Uncommon (>1/1000, <1/100): Refraction Disorders: Refraction anomalies may occur upon initiation of insulin therapy. These symptoms are usually of transitory nature.
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 temporary worsening of diabetic retinopathy.
Nervous System Disorders: Rare (>1/10,000, <1/1000): Peripheral Neuropathy: Fast improvement in blood glucose control may be associated with the condition “acute painful neuropathy”, which is usually reversible.
Drug Interactions
A number of medicinal products are known to interact with the glucose metabolism.
The following substances may reduce the insulin requirements: Oral antidiabetic drugs, monoamine oxidase inhibitors (MAOI), nonselective β-blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates and alcohol.
The following substances may increase the insulin requirements: Thiazides, glucocorticoids, thyroid hormones and β-sympathomimetics, growth hormone and danazol.
Beta-blocking agents may mask the symptoms of hypoglycaemia and delay recovery from hypoglycaemia.
Octreotide/lanreotide may both increase and decrease insulin requirement.
Alcohol may intensify and prolong the hypoglycaemic effect of insulin.
Incompatibilities: Substances added to Levemir may cause degradation of insulin detemir eg, if the medicinal product contains thiols or sulfites. Levemir should not be added to infusion fluids.
Storage
Levemir FlexPen in use should not be kept in a refrigerator. Levemir FlexPen in use or carried as a spare should be kept at ambient temperature (not above 30°C) for up to 6 weeks.
Store Levemir FlexPen, which is not in use at 2°C-8°C (in a refrigerator) not near a freezing compartment. Do not Freeze.
In order to protect from light keep the pen cap on when Levemir FlexPen is not in use.
ATC Classification
A10AE05 - insulin detemir ; Belongs to the class of long-acting insulins and analogues for injection. Used in the treatment of diabetes.
Presentation/Packing
FlexPen (clear, colourless, neutral soln) 100 units/mL x 3 mL x 5's.
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