4.1. Therapeutic indications

Treatment of diabetes mellitus in adults, adolescents and children from the age of 1 year.

4.2. Posology and method of administration

Posology

This medicinal product is a basal insulin for once-daily subcutaneous administration at any time of the day, preferably at the same time every day.

The potency of insulin analogues, including insulin degludec, is expressed in units. One (1) unit of insulin degludec corresponds to 1 international unit of human insulin, 1 unit of insulin glargine (100 units/mL), or 1 unit of insulin detemir.

In patients with type 2 diabetes mellitus, this medicinal product can be administered alone or in any combination with oral antidiabetic medicinal products, GLP-1 receptor agonists and bolus insulin (see section 5.1).

In type 1 diabetes mellitus, Tresiba must be combined with short-/rapid-acting insulin to cover mealtime insulin requirements.

Tresiba is to be dosed in accordance with the individual patient's needs. It is recommended to optimise glycaemic control via dose adjustment based on fasting plasma glucose.

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

Flexibility in dosing time

On occasions when administration at the same time of the day is not possible, Tresiba allows for flexibility in the timing of insulin administration (see section 5.1). A minimum of 8 hours between injections should always be ensured. There is no clinical experience with flexibility in dosing time of Tresiba in children and adolescents.

Patients who forget a dose are advised to take it upon discovery and then resume their usual once-daily dosing schedule.

Initiation

Patients with type 2 diabetes mellitus

The recommended daily starting dose is 10 units followed by individual dosage adjustments.

Patients with type 1 diabetes mellitus

Tresiba is to be used once daily with mealtime insulin and requires subsequent individual dosage adjustments.

Transfer from other insulin medicinal products

Close glucose monitoring is recommended during the transfer and in the following weeks. Doses and timing of concurrent rapid-acting or short-acting insulin products or other concomitant antidiabetic treatment may need to be adjusted.

Patients with type 2 diabetes mellitus

For patients with type 2 diabetes taking once-daily basal, basal-bolus, premix or self-mixed insulin therapy, changing the basal insulin to Tresiba can be done unit-to-unit based on the previous basal insulin dose followed by individual dosage adjustments.

A dose reduction of 20% based on the previous basal insulin dose followed by individual dosage adjustments should be considered when

- transferring to Tresiba from twice-daily basal insulin

- transferring to Tresiba from insulin glargine (300 units/mL)

Patients with type 1 diabetes mellitus

For patients with type 1 diabetes a dose reduction of 20% based on the previous basal insulin dose or basal component of a continuous subcutaneous insulin infusion regimen should be considered with subsequent individual dosage adjustments based on the glycaemic response.

Use of Tresiba in combination with GLP-1 receptor agonists in patients with type 2 diabetes mellitus

When adding Tresiba to GLP-1 receptor agonists, the recommended daily starting dose is 10 units followed by individual dosage adjustments.

When adding GLP-1 receptor agonists to Tresiba, it is recommended to reduce the dose of Tresiba by 20% to minimise the risk of hypoglycaemia. Subsequently, dosage should be adjusted individually.

Special populations

Elderly (≥65 years old)

Tresiba can be used in elderly. Glucose monitoring is to be intensified and the insulin dose adjusted on an individual basis (see section 5.2).

Renal and hepatic impairment

Tresiba can be used in renal and hepatic impaired patients. Glucose monitoring is to be intensified and the insulin dose adjusted on an individual basis (see section 5.2).

Paediatric population

There is no clinical experience with the use of this medicinal product in children below the age of 1 year. This medicinal product can be used in adolescents and children from the age of 1 year (see section 5.1). When changing basal insulin to Tresiba, dose reduction of basal and bolus insulin needs to be considered on an individual basis in order to minimise the risk of hypoglycaemia (see section 4.4).

Method of administration

Subcutaneous use only.

Tresiba must not be administered intravenously as it may result in severe hypoglycaemia.

This medicinal product must not be administered intramuscularly as it may change the absorption.

This medicinal product must not be used in insulin infusion pumps.

Tresiba must not be drawn from the cartridge of the pre-filled pen into a syringe (see section 4.4).

Tresiba is administered subcutaneously by injection in the thigh, the upper arm or the abdominal wall. Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see sections 4.4 and 4.8).

Patients should be instructed to always use a new needle. The re-use of insulin pen needles increases the risk of blocked needles, which may cause under- or overdosing. In the event of blocked needles, patients must follow the instructions described in the instructions for use accompanying the package leaflet (see section 6.6).

Tresiba comes in a cartridge (Penfill) designed to be used with Novo Nordisk insulin delivery systems and NovoFine or NovoTwist injection needles.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Hypoglycaemia

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

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement (see sections 4.5, 4.8 and 4.9).

In children, care should be taken to match insulin doses (especially in basal-bolus regimens) with food intake and physical activities in order to minimise the risk of hypoglycaemia.

Patients whose blood glucose control is greatly improved (e.g. by intensified insulin therapy) may experience a change in their usual warning symptoms of hypoglycaemia and must be advised accordingly. Usual warning symptoms may disappear in patients with long-standing diabetes.

Concomitant illness, especially infections and fever, usually increases the patient's insulin requirement. Concomitant diseases in the kidney, liver or diseases affecting the adrenal, pituitary or thyroid gland may require changes in the insulin dose.

As with other basal insulin products, the prolonged effect of Tresiba may delay recovery from hypoglycaemia.

Hyperglycaemia

Administration of rapid-acting insulin is recommended in situations with severe hyperglycaemia.

Inadequate dosing and/or discontinuation of treatment in patients requiring insulin may lead to hyperglycaemia and potentially to diabetic ketoacidosis. Furthermore, concomitant illness, especially infections, may lead to hyperglycaemia and thereby cause an increased insulin requirement.

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, and loss of appetite as well as acetone odour of breath. In type 1 diabetes mellitus, untreated hyperglycaemic events eventually lead to diabetic ketoacidosis, which is potentially lethal.

Transfer from other insulin medicinal products

Transferring a patient to another type, brand or manufacturer of insulin must be done under medical supervision and may result in the need for a change in dosage.

Skin and subcutaneous tissue disorders

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site from an affected to an unaffected area, and dose adjustment of antidiabetic medications may be considered.

Combination of pioglitazone and insulin medicinal products

Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac failure. This should be kept in mind if treatment with the combination of pioglitazone and Tresiba is considered. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.

Eye disorder

Intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy, while long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy.

Avoidance of medication errors

Patients must be instructed to always check the insulin label before each injection to avoid accidental mix-ups between the two different strengths of Tresiba as well as other insulin products.

Patients must visually verify the dialled units on the dose counter of the pen. Therefore, the requirement for patients to self-inject is that they can read the dose counter on the pen. Patients who are blind or have poor vision must be instructed to always get help/assistance from another person who has good vision and is trained in using the insulin device.

To avoid dosing errors and potential overdose, patients and healthcare professionals should never use a syringe to draw the medicinal product from the cartridge in the pre-filled pen.

In the event of blocked needles, patients must follow the instructions described in the instructions for use accompanying the package leaflet (see section 6.6).

Insulin antibodies

Insulin administration may cause insulin antibodies to form. In rare cases, the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyper‑ or hypoglycaemia.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially 'sodium-free'.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

4.5. Interaction with other medicinal products and other forms of interaction

A number of medicinal products are known to interact with glucose metabolism.

The following substances may reduce the insulin requirement

Oral antidiabetic medicinal products, GLP‑1 receptor agonists, monoamine oxidase inhibitors (MAOI), beta‑blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulfonamides.

The following substances may increase the insulin requirement

Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol.

Beta‑blockers may mask the symptoms of hypoglycaemia.

Octreotide/lanreotide may either increase or decrease the insulin requirement.

Alcohol may intensify or reduce the hypoglycaemic effect of insulin.

4.6. Fertility, pregnancy and lactation

Pregnancy

The use of Tresiba in pregnant women with diabetes has been investigated in an interventional trial (see section 5.1). A moderate amount of clinical trial and post-marketing data in pregnant women (more than 400 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity. Animal reproduction studies have not revealed any difference between insulin degludec and human insulin regarding embryotoxicity and teratogenicity.

The treatment with Tresiba may be considered during pregnancy, if clinically needed.

In general, intensified blood glucose control and monitoring of pregnant women with diabetes are recommended throughout pregnancy and when contemplating pregnancy. Insulin requirements usually decrease in the first trimester and increase subsequently during the second and third trimesters. After delivery, insulin requirements usually return rapidly to pre-pregnancy values. Careful monitoring of glucose control is recommended and the insulin dose adjusted on an individual basis.

Breast-feeding

There is no clinical experience with Tresiba during breast-feeding. In rats, insulin degludec was secreted in milk; the concentration in milk was lower than in plasma.

It is unknown whether insulin degludec is excreted in human milk. No metabolic effects are anticipated in the breast-fed newborn/infant.

Fertility

Animal reproduction studies with insulin degludec have not revealed any adverse effects on fertility.

4.7. Effects on ability to drive and use machines

This medicinal product has no or negligible influence on the ability to drive and use machines. However, 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 using machines).

Patients must 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.

4.8. Undesirable effects

Summary of the safety profile

The most frequently reported adverse reaction during treatment is hypoglycaemia (see section 'Description of selected adverse reactions' below).

Tabulated list of adverse reactions

Adverse reactions listed below are based on clinical trial data and classified according to MedDRA System Organ Class. Frequency categories are defined according to the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data).

System organ class

Frequency

Adverse reaction

Immune system disorders

Rare

Hypersensitivity

Urticaria

Metabolism and nutrition disorders

Very common

Hypoglycaemia

Skin and subcutaneous tissue disorders

Uncommon

Lipodystrophy

Not known

Cutaneous amyloidosis†

General disorders and administration site conditions

Common

Injection site reactions

Uncommon

Peripheral oedema

† ADR from postmarketing sources.

Description of selected adverse reactions

Immune system disorders

With insulin preparations, allergic reactions may occur. Immediate-type allergic reactions to either insulin itself or the excipients may potentially be life-threatening.

With Tresiba, hypersensitivity (manifested with swelling of tongue and lips, diarrhoea, nausea, tiredness and itching) and urticaria were reported rarely.

Hypoglycaemia

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death. The 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.

Skin and subcutaneous tissue disorders

Lipodystrophy (including lipohypertrophy, lipoatrophy) and cutaneous amyloidosis may occur at the injection site and delay local insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions (see section 4.4).

Injection site reactions

Injection site reactions (including injection site haematoma, pain, haemorrhage, erythema, nodules, swelling, discolouration, pruritus, warmth and injection site mass) occurred in patients treated with Tresiba. These reactions are usually mild and transitory and they normally disappear during continued treatment.

Paediatric population

Tresiba has been administered to children and adolescents up to 18 years of age for the investigation of pharmacokinetic properties (see section 5.2). Safety and efficacy have been demonstrated in a long term trial in children aged 1 to less than 18 years. The frequency, type and severity of adverse reactions in the paediatric population do not indicate differences to the experience in the general diabetes population (see section 5.1).

Other special populations

Based on results from clinical trials, the frequency, type and severity of adverse reactions observed in elderly and in patients with renal or hepatic impairment do not indicate any differences to the broader experience in the general population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

Yellow Card Scheme

Website: https://yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

A specific overdose for insulin cannot be defined. However, hypoglycaemia may develop over sequential stages if a patient is dosed with more insulin than required:

• Mild hypoglycaemic episodes can be treated by oral administration of glucose or other products containing sugar. It is therefore recommended that the patient always carries glucose‑containing products.

• Severe hypoglycaemic episodes, where the patient is not able to treat himself, can be treated with glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, or with glucose given intravenously by a healthcare professional. Glucose must 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.