Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Novo Nordisk A/S, Novo Alle 1, DK-2880 Bagsvaerd, Denmark
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
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).
Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.
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.
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. The possibility of recurrent, unrecognised (especially nocturnal) episodes of hypoglycaemia must be considered.
Patient adherence to the dose and dietary regimen, correct insulin administration and awareness of hypoglycaemia symptoms are essential to reduce the risk of hypoglycaemia. Factors increasing the susceptibility to hypoglycaemia require particularly close monitoring. These include:
The prolonged effect of Awiqli may delay recovery from hypoglycaemia. Upon onset of a hypoglycaemic episode, patient is recommended to closely measure blood glucose until recovery.
For type 1 diabetes patients treated with insulin icodec there was a higher risk of hypoglycaemia compared to insulin degludec (see sections 4.8 and 5.1). Patients with type 1 diabetes should only be treated with insulin icodec if a clear benefit from a once weekly posology is expected.
The safety and efficacy of insulin icodec in newly diagnosed insulin-naïve type 1 diabetes patients have not been established. No data are available.
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, loss of appetite as well as acetone odour of breath. Untreated hyperglycaemia may eventually lead to diabetic ketoacidosis, which is potentially lethal.
Switching a patient between another insulin medicinal product and insulin icodec should be done under medical supervision and may result in the need for a change in dosage (see section 4.2).
During switch from daily basal insulin to weekly insulin icodec, medication errors can occur in the form of e.g., overdose, dosing errors or forgetting to remove the recommended one-time additional dose after the first injection. These errors might result in hypoglycaemia, hyperglycaemia and/or other clinical consequences. Therefore, patients must be instructed to check that they inject the correct dose, especially for the first and second injections (see sections 4.2 and 4.9).
Patients who are uncertain about the correct dose must be instructed to consult their physician for further guidance.
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 medicinal products may be considered.
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.
Patients must be instructed to always check the label on the insulin pen before each injection to avoid accidental mix-ups between once-weekly insulin icodec and other insulin products. Patients must visually verify the dialled units on the dose counter of the pre-filled 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 pre-filled pen.
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.
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 (see sections 5.1 and 5.2).
Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of congestive heart failure. This should be kept in mind if treatment with the combination of pioglitazone and insulin icodec is considered. If the combination is used, patients should be observed for signs and symptoms of congestive heart failure, weight gain, and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., it is essentially ‘sodium-free’.
A number of medicinal products are known to interact with glucose metabolism.
Medicinal products that may reduce the insulin requirement
Antidiabetic medicinal products, GLP-1 receptor agonists, sulfonylurea, 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.
Octreotide/lanreotide may either increase or decrease the insulin requirement.
Alcohol may intensify or reduce the hypoglycaemic effect of insulin.
Beta-blockers may mask the symptoms of hypoglycaemia.
There is no clinical experience with use of insulin icodec in pregnant women.
Animal reproduction studies with insulin icodec have not revealed any effects regarding embryotoxicity and teratogenicity.
Because of lack of experience during pregnancy, women of childbearing potential should be advised to discontinue Awiqli, if they become pregnant or wish to become pregnant.
It is unknown whether insulin icodec is excreted in human milk. Available pharmacodynamic/toxicological data in rats have shown excretion of insulin icodec in milk. A risk to the newborns/infants cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from insulin icodec therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Animal reproduction studies with insulin icodec have not revealed any adverse reactions on fertility.
Awiqli has no or negligible influence on the ability to drive and use machines. The patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia or hyperglycaemia or, for example, as a result of visual impairment. 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.
The most frequently reported adverse reaction during clinical trials with insulin icodec is hypoglycaemia (see sections 4.4 and 5.1).
The overall safety profile of insulin icodec is based on six phase 3 (ONWARDS 1-6) trials where a total of 2 170 patients were exposed to insulin icodec, 1 880 with type 2 diabetes and 290 with type 1 diabetes.
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).
Table 2. Tabulated list of adverse reactions:
| MedDRA system organ classes | Very common | Common | Uncommon | Rare |
|---|---|---|---|---|
| Immune system disorders | Hypersensitivity*** | |||
| Metabolism and nutrition disorders | Hypoglycaemia* | |||
| General disorders and administration site conditions | Injection site reaction Peripheral oedema** | |||
| Skin and subcutaneous tissue disorders | Lipodystrophy |
* Hypoglycaemia is defined below.
** Grouped term covering adverse events related to peripheral oedema.
*** Grouped term covering adverse events related to hypersensitivity.
Hypoglycaemia is the most commonly observed adverse drug reaction in patients using insulin icodec (see sections 4.4 and 5.1).
In phase 3 clinical trials with insulin icodec, severe hypoglycaemia was defined as hypoglycaemia associated with severe cognitive impairment requiring external assistance for recovery and clinically significant hypoglycaemia was defined as plasma glucose value less than 54 mg/dL (3.0 mmol/L).
The proportion of patients reporting severe or clinically significant hypoglycaemic episodes for insulin icodec vs daily basal insulin was 9%-12% vs 6%-11% in insulin naïve type 2 diabetes patients (ONWARDS 1, 3 and 5), 14% vs 7% in type 2 diabetes patients previously treated with basal insulin (ONWARDS 2), and 51% vs 56% in type 2 diabetes patients previously on basal-bolus insulin regimen (ONWARDS 4).
The rates of severe or clinically significant hypoglycaemic episodes per PYE for insulin icodec vs daily basal insulin were as follows: ONWARDS 1: 0.30 vs 0.16; ONWARDS 3: 0.31 vs 0.15; ONWARDS 5: 0.19 vs 0.14 (insulin naïve type 2 diabetes patients); ONWARDS 2: 0.73 vs 0.27 (type 2 diabetes patients previously treated with basal insulin); and ONWARDS 4: 5.64 vs 5.62 (type 2 diabetes patients previously on basal-bolus insulin regimen).
The main phase of ONWARDS 1 trial was followed by an extension part of 26 weeks treatment duration in order to investigate long-term safety. In the complete trial, the proportion of patients with severe or clinically significant hypoglycaemic episodes for insulin icodec vs insulin glargine 100 units/mL was 12% vs 14%, and the rate was 0.30 vs 0.16 episodes per PYE.
For information on daily basal insulin comparators used in each trial, please see section 5.1.
The proportion of patients reporting severe or clinically significant hypoglycaemic episodes for insulin icodec vs insulin degludec was 85% vs 76% in previously basal insulin-treated patients with type 1 diabetes. The rate of severe or clinically significant hypoglycaemic episodes per PYE for insulin icodec compared to insulin degludec was 19.93 vs 10.37.
ONWARDS 6 trial was followed by an extension part of 26 weeks treatment duration in order to investigate long-term safety. In the complete trial, the proportion of patients with severe or clinically significant hypoglycaemic episodes for insulin icodec vs insulin degludec was 91% vs 86%, and the rate was 17.00 vs 9.16 episodes per PYE.
See also section 5.1.
Across the ONWARDS trials, most hypoglycaemic episodes were observed day 2-4 after the weekly administration.
As with other insulins, allergic reactions may occur with insulin icodec. Immediate-type allergic reactions to either insulin itself or the excipients may potentially be life-threatening.
Hypersensitivity reactions (such as urticaria, lip swelling and swelling face) have been reported in the phase 3a program with insulin icodec. Hypersensitivity reactions were reported in 0.4% of insulin icodec-treated patients compared to 0.6% of daily basal insulin-treated patients. Two out of the 10 events reported by insulin icodec-treated patients were severe (urticaria) and one of these was also reported as serious.
In the phase 3 trials, injection site reactions were reported in 1.6% of insulin icodec-treated patients compared to 1.4% of daily basal insulin-treated patients. The majority of injection site reactions in the insulin icodec-treated patients (75%) were reported in the double-blinded, double-dummy, activecontrolled trial (ONWARDS 3). In the daily basal insulin-treated patients, 21% of injection site reactions were reported in ONWARDS 3.
Overall, in the phase 3 trials, the most common signs and symptoms of injection site reactions were erythema and pruritus. The maximum severity of injection site reactions for patients treated with insulin icodec was mild (94%) or moderate (6%). No injection site reactions were serious.
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).
Based on results from clinical trials with insulin icodec, the frequency, type and severity of adverse reactions observed in elderly patients and in patients with renal or hepatic impairment do not in general indicate any differences to the broader experience in the overall insulin icodec-treated population.
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 the national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products.
Awiqli must not be added to infusion fluids.
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