Tresiba FlexTouch

Each mL of solution contains insulin degludec* 100 units (equivalent to insulin degludec 3.66 mg). One pre-filled pen contains insulin degludec 300 units in 3 mL solution.
*Produced in Saccharomyces cerevisiae by recombinant DNA technology.
It contains the following excipients: glycerol, metacresol, phenol, zinc acetate, hydrochloric acid/sodium hydroxide (for pH adjustment) and water for injections.

Pharmacotherapeutic Group: Drugs used in diabetes. Insulins and analogs for injection, long-acting. ATC Code: A10AE06.
Pharmacology: Pharmacodynamics: Mechanism of Action: Insulin degludec binds specifically to the human insulin receptor and results in the same pharmacological effects as human insulin.
The blood glucose-lowering effect of insulin is due to the facilitated uptake of glucose following the binding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucose output from the liver.
Pharmacodynamic Effects: Insulin degludec is a basal insulin that forms soluble multi-hexamers upon SC injection, resulting in a depot from which insulin degludec is continuously and slowly absorbed into the circulation leading to a flat and stable glucose-lowering effect of insulin degludec (see figure). During a period of 24 hrs with once-daily treatment, the glucose-lowering effect of insulin degludec, in contrast to insulin glargine, was evenly distributed between the 1st and 2nd 12 hrs (AUC_GIR,0-12hr,_SS/AUCG_IR,total,SS=0.5).

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The duration of action of insulin degludec is beyond 42 hrs within the therapeutic dose range. Steady state will occur after 2-3 days of dose administration.
The insulin degludec glucose-lowering action at steady state, shows 4 times lower day-to-day variability in terms of Coefficients of Variation (CV) for the glucose-lowering effect during 0-24 hrs (AUC_GIR,τ,SS) and 2-24 hrs (AUC_GIR2-24hr,SS) as compared to insulin glargine, see Table 1.

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Total glucose-lowering effect of insulin degludec increases linearly with increasing doses.
There is no clinically relevant difference in the pharmacodynamics of insulin degludec between elderly and younger adult patients.
Clinical Efficacy and Safety: Eleven (11) multinational clinical trials of 26 or 52 weeks' duration were conducted as controlled, open-label, randomized, parallel, treat-to-target trials exposing 4,275 patients to insulin degludec [1,102 in type 1 diabetes mellitus (DM) and 3,173 in type 2 DM].
The effect of insulin degludec was tested in patients with type 1 DM (see Table 3), in insulin naive patients (insulin initiation in type 2 DM, see Table 4) and in previous insulin users (insulin intensification in type 2 DM, see Table 5) with fixed as well as flexible dosing time (see Table 6), and the reduction in HbA_1c from baseline to end of trial was confirmed to be non-inferior in all trials against all comparators (insulin detemir and insulin glargine). While improvements in HbA_1c were non-inferior compared to other insulin products, against sitagliptin insulin degludec was statistically significantly superior in reducing HbA_1c (see Table 5).
In a prospectively planned meta-analysis across 7 treat-to-target confirmatory trials in patients with type 1 and type 2 DM, insulin degludec was superior in terms of a lower number of treatment emergent confirmed hypoglycemic episodes (driven by a benefit in type 2 DM, see Table 2) and nocturnal confirmed hypoglycemic episodes compared to insulin glargine (administered according to label). The reduction in hypoglycemia was achieved at a lower average fasting plasma glucose (FPG) level with insulin degludec than with insulin glargine.

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There is no clinically relevant development of insulin antibodies after long-term treatment with insulin degludec.

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Pharmacokinetics: Absorption: After SC injection, soluble and stable multi-hexamers are formed creating a depot of insulin in the SC tissue. Insulin degludec monomers gradually separate from the multi-hexamers thus resulting in a slow and continuous delivery of insulin degludec into the circulation.
Steady state serum concentration is reached after 2-3 days of daily insulin degludec administration.
During a period of 24 hrs with once-daily treatment, the exposure of insulin degludec was evenly distributed between the 1st and 2nd 12 hrs. The ratio between AUC_{GIR,0-12hr,SS} and AUC_GIR,τ,SS was 0.5.
Distribution: The affinity of insulin degludec to serum albumin corresponds to a plasma protein-binding of >99% in human plasma.
Biotransformation: Degradation of insulin degludec is similar to that of human insulin; all metabolites formed are inactive.
Elimination: The half-life (t_½) after SC administration of insulin degludec is determined by the rate of absorption from the subcutaneous tissue. The t_½ of insulin degludec is approximately 25 hrs independent of dose.
Linearity: Dose proportionality in total exposure is observed after SC administration within the therapeutic dose range.
Gender: There is no gender difference in the pharmacokinetic properties of insulin degludec.
Elderly, Race, Renal and Hepatic Impairment: There is no difference in the pharmacokinetics of insulin degludec between elderly and younger adult patients, between races or between healthy subjects and patients with renal or hepatic impairment.
Pediatric Population: Pharmacokinetic properties of insulin degludec were investigated in children (6-11 years) and adolescents (12-18 years), and were comparable to those observed in adults with type 1 DM. Total exposure after a single dose is however, higher in children and adolescents than in adults with type 1 DM.
Toxicology: Preclinical Safety Data: Nonclinical data reveal no safety concerns for humans based on studies of safety pharmacology, repeated dose toxicity, carcinogenic potential and toxicity to reproduction.
The ratio of mitogenic relative to metabolic potency for insulin degludec is comparable to that of human insulin.

Treatment of diabetes mellitus (DM) in adults.
The treatment with Insulin Degludec may be considered during pregnancy, if clinically needed.

Insulin degludec is a basal insulin for once-daily SC administration at any time of the day, preferably at the same time every day.
The potency of insulin analogs, including insulin degludec, is expressed in units (U). One (1) unit of insulin degludec corresponds to 1 international unit (IU) of human insulin, 1 unit of insulin glargine or 1 unit of insulin detemir.
In patients with type 2 DM, insulin degludec can be administered alone, in combination with oral anti-diabetic medicinal products as well as in combination with bolus insulin (see Pharmacology: Pharmacodynamics).
In type 1 DM, insulin degludec must be combined with short-/rapid-acting insulin to cover mealtime insulin requirements.
Insulin degludec is to be dosed in accordance with the individual patient's needs. It is recommended to optimize glycemic control via dose adjustment based on fasting plasma glucose. As with all insulin products adjustment of dose may be necessary if patients undertake increased physical activity, change their usual diet or during concomitant illness.
Insulin degludec 100 units/mL: The needed dose is dialed in units. With insulin degludec 100 units/mL a dose of 1-80 units/injection, in steps of 1 unit, can be administered.
The dose counter shows the number of units.
Flexibility in Dosing Time: On occasions when administration at the same time of the day is not possible, insulin degludec allows for flexibility in the timing of insulin administration (see Pharmacology: Pharmacodynamics). A minimum of 8 hrs between injections should always be ensured.
Patients who forget a dose are advised to take it upon discovery and then resume their usual once-daily dosing schedule.
Type 2 DM: Recommended Daily Starting Dose: 10 units followed by individual dosage adjustments.
Type 1 DM: Insulin degludec is to be used once-daily with meal-time 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 anti-diabetic treatment may need to be adjusted.
Type 2 DM: For patients with type 2 diabetes taking basal, basal-bolus, premix or self-mixed insulin therapy, changing the basal insulin to insulin degludec can be done unit-to-unit based on the previous basal insulin dose followed by individual dosage adjustments.
Type 1 DM: For most patients with type 1 diabetes, changing the basal insulin to insulin degludec can be done unit-to-unit based on the previous basal insulin dose with subsequent individual dosage adjustments. For patients with type 1 diabetes transferring from twice-daily basal insulin or having Hb_A1c <8% at the time of transfer, the dose of insulin degludec needs to be determined on an individual basis. Dose reduction needs to be considered followed by individual dosage adjustment based on the glycemic response.
Special Populations: Elderly (≥65 years): Insulin degludec can be used in elderly patients. Glucose-monitoring is to be intensified and the insulin dose adjusted on an individual basis (see Pharmacology: Pharmacokinetics).
Renal and Hepatic Impairment: Insulin degludec 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 Pharmacology: Pharmacokinetics).
Administration: Insulin degludec is for SC use only. It must not be administered IV as it may result in severe hypoglycemia. It must not be administered IM as it may change the absorption and it must not be used in insulin infusion pumps.
Insulin degludec is administered SC by injection in the thigh, the upper arm or the abdominal wall. Injection sites are always to be rotated within the same region in order to reduce the risk of lipodystrophy. Insulin degludec comes in a pre-filled pen designed to be used with NovoFine or NovoTwist injection needles.
The 100 units/mL pre-filled pen delivers 1-80 units in steps of 1 unit.

A specific overdosage for insulin cannot be defined; however, hypoglycemia may develop over sequential stages if a patient is dosed with more insulin than required.
Mild hypoglycemic 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 hypoglycemic episodes, where the patient is not able to treat himself, can be treated with glucagon (0.5-1 mg) given IM or SC by a trained person, or with glucose given IV by a healthcare professional. Glucose must be given IV, if the patient does not respond to glucagon within 10-15 min. Upon regaining consciousness, administration of oral carbohydrates is recommended for the patient in order to prevent a relapse.

Hypersensitivity to insulin degludec or to any of the excipients of Tresiba FlexTouch.

Hypoglycemia: Omission of a meal or unplanned strenuous physical exercise may lead to hypoglycemia.
Hypoglycemia may occur if the insulin dose is too high in relation to the insulin requirement.
Patients whose blood-glucose control is greatly improved (eg, by intensified insulin therapy) may experience a change in their usual warning symptoms of hypoglycemia 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 insulin degludec may delay recovery from hypoglycemia.
Hyperglycemia: Administration of rapid-acting insulin is recommended in situations with severe hyperglycemia.
Inadequate dosing and/or discontinuation of treatment in patients requiring insulin may lead to hyperglycemia and potentially to diabetic ketoacidosis. Furthermore, concomitant illness, especially infections, may lead to hyperglycemia and thereby cause an increased insulin requirement. Usually, the 1st symptoms of hyperglycemia 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 odor of breath. In type 1 DM, untreated hyperglycemic events eventually lead to diabetic ketoacidosis, which is potentially lethal.
Transfer from Other Insulin 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.
Combination of Thiazolidinediones and Insulin Medicinal Products: Cases of cardiac failure have been reported when thiazolidinediones were 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 thiazolidinediones and insulin degludec is considered. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and edema. Thiazolidinediones should be discontinued if any deterioration in cardiac symptoms occurs.
Eye Disorder: Intensification of insulin therapy with abrupt improvement in glycemic control may be associated with temporary worsening of diabetic retinopathy, while long-term improved glycemic 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 2 different strengths of insulin degludec as well as other insulin products. Patients must visually verify the dialed 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.
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 hyperglycemia or hypoglycemia.
Effects on the Ability to Drive and Operate Machinery: 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 (eg, driving a car or operating machines).
Patients must be advised to take precautions to avoid hypoglycemia while driving. This is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycemia or have frequent episodes of hypoglycemia. The advisability of driving should be considered in these circumstances.
Impairment of Fertility: Animal reproduction studies with insulin degludec have not revealed any adverse effects on fertility.
Use in Children: The safety and efficacy of insulin degludec in children and adolescents <18 years have not been established. Currently available data are described in Pharmacology: Pharmacokinetics, but no recommendation on a dosage can be made.
Insulin Degludec may be given to children ages 1 year old and above.
Use in Pregnancy & Lactation: The use of Insulin Degludec in pregnant women with diabetes has been investigated in an interventional trial (EXPECT Trial). A moderate amount of clinical trial and post-marketing data in pregnant women indicate no malformative or feto/neonatal toxicity. The treatment with Insulin Degludec may be considered during pregnancy, if clinically needed.
There is no clinical experience with Insulin Degludec during breast-feeding.

The use of Insulin Degludec in pregnant women with diabetes has been investigated in an interventional trial (EXPECT Trial). A moderate amount of clinical trial and post-marketing data in pregnant women indicate no malformative or feto/neonatal toxicity. The treatment with Insulin Degludec may be considered during pregnancy, if clinically needed.
There is no clinical experience with Insulin Degludec during breast-feeding.

Summary of the Safety Profile: The most frequently reported adverse reaction during treatment is hypoglycemia (see Description of Selected Adverse Reactions as follows).
Tabulated List of Adverse Reactions: Adverse reactions listed as follows 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 (≥1/1000 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).

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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 insulin degludec, hypersensitivity (manifested with swelling of tongue and lips, diarrhea, nausea, tiredness and itching) and urticaria were reported rarely.
Hypoglycemia: Hypoglycemia may occur if the insulin dose is too high in relation to the insulin requirement. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death. The symptoms of hypoglycemia 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.
Lipodystrophy: Lipodystrophy (including lipohypertrophy, lipoatrophy) may occur at the injection site. Continuous rotation of the injection site within the particular injection area may help to reduce the risk of developing these reactions.
Injection Site Reactions: Injection site reactions (including injection site hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth and injection site mass) occurred in patients treated with insulin degludec. These reactions are usually mild and transitory, and they normally disappear during continued treatment.
Pediatric Population: Insulin degludec has been administered to children and adolescents up to 18 years for the investigation of pharmacokinetic properties (see Pharmacology: Pharmacokinetics). Safety and efficacy have not been established in children and adolescents.
Other Special Populations: Based on results from clinical trials, the frequency, type and severity of adverse reactions observed in elderly patients and in patients with renal or hepatic impairment do not indicate any differences to the broader experience in the general population.

A number of medicinal products are known to interact with glucose metabolism.
The following substances may reduce the insulin requirement: Oral anti-diabetic medicinal products, GLP-1 receptor agonists, monoamine oxidase inhibitors (MAOIs), β-blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulphonamides.
The following substances may increase the insulin requirement: Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol.
β-blockers may mask the symptoms of hypoglycemia. Octreotide/lanreotide may either increase or decrease the insulin requirement.
Alcohol may intensify or reduce the hypoglycemic effect of insulin.

Incompatibilities: Substances added to insulin degludec may cause degradation of insulin degludec. It must not be added to infusion fluids and must not be mixed with any other product.
Instructions for Use, Handling and Disposal: The pre-filled pen (FlexTouch) is designed to be used with NovoFine or NovoTwist injection needles up to a length of 8 mm. It delivers 1-80 units in steps of 1 unit. Detailed instructions accompanying the pre-filled pen must be followed.
The pre-filled pen (FlexTouch) is for use by one person only. The pre-filled pen must not be refilled.
Insulin degludec must not be used if the solution does not appear clear and colorless. Insulin degludec which has been frozen must not be used.
The patient should discard the needle after each injection.
Any waste material should be disposed of in accordance with local requirements. For detailed instructions for use, see package leaflet.

Before 1st Use: Store in a refrigerator (2-8°C). Keep away from the freezing element. Do not freeze. Keep the cap on the pen in order to protect from light.
After 1st Opening or Carried as a Spare: Do not refrigerate. Do not store above 30°C. Keep the cap on the pen in order to protect from light.
Shelf-Life: 30 months. After 1st opening, the product may be stored for a maximum of 8 weeks. Do not store above 30°C. Do not refrigerate.

Insulin Preparations

A10AE06 - insulin degludec ; Belongs to the class of long-acting insulins and analogues for injection. Used in the treatment of diabetes.

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