Insulin icodec interacts in the following cases:
No dose adjustment is required for patients with hepatic impairments. In patients with hepatic impairment, more frequent glucose monitoring is recommended.
No dose adjustment is required for patients with renal impairment. In patients with renal impairment, more frequent glucose monitoring is recommended.
Alcohol may intensify or reduce the hypoglycaemic effect of insulin.
Antidiabetic medicinal products, GLP-1 receptor agonists, sulfonylurea, monoamine oxidase inhibitors (MAOI), beta-blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids, and sulfonamides.
Beta-blockers may mask the symptoms of hypoglycaemia.
Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol.
Octreotide/lanreotide may either increase or decrease the insulin requirement.
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.
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.
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.
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 insulin icodec, 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.
Insulin icodec 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.
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.
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.
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.
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.
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.
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