Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands
Hypoglycaemia.
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 medicinal product should be clearly recorded.
Hypoglycaemia is the most common adverse reaction of insulin therapy. The timing of hypoglycaemia usually reflects the time-action profile of the administered insulin formulations. Hypoglycaemia may occur earlier after an injection/infusion when compared to other mealtime insulins due to the earlier onset of action of Lyumjev (see section 5.1).
Hypoglycaemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Severe hypoglycaemia can cause seizures, may lead to unconsciousness, may be life-threatening, or cause death. Symptomatic awareness of hypoglycaemia may be less pronounced in patients with longstanding diabetes.
The use of inadequate doses or discontinuation of treatment, may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal.
Patients should be educated to recognize the signs and symptoms of ketoacidosis and to get immediate help when ketoacidosis is suspected.
Changes in insulin, insulin concentration, manufacturer, type, or method of administration may affect glycaemic control and predispose to hypoglycaemia or hyperglycaemia. These changes should be made cautiously under close medical supervision and the frequency of glucose monitoring should be increased. For patients with type 2 diabetes, dosage adjustments in concomitant anti-diabetic treatment may be needed (see sections 4.2 and 4.5).
In patients with renal or hepatic impairment, glucose monitoring should be intensified and dosage adjusted on an individual basis (see section 4.2).
Insulin requirements may be increased during illness or emotional disturbances.
Adjustment of dosage may also be necessary if patients undertake increased physical activity or change their usual diet. Exercise taken immediately after a meal may increase the risk of hypoglycaemia.
Malfunction of the insulin pump or insulin infusion set can rapidly lead to hyperglycaemia and ketoacidosis. Prompt identification and correction of the cause of hyperglycaemia or ketosis is necessary. Interim subcutaneous injections with Lyumjev may be required.
TZDs can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin and a TZD should be observed for signs and symptoms of heart failure. If heart failure develops, consider discontinuation of the TZD.
Severe, life-threatening, generalised allergy, including anaphylaxis, can occur with insulin medicinal products, including Lyumjev. If hypersensitivity reactions occur, discontinue Lyumjev.
Lyumjev should not be used by patients with visual impairment without help of a trained person.
To avoid medication errors between Lyumjev and other insulins, patients need to always check the insulin label before each injection.
Patients should always use a new needle for each injection to prevent infections and a blocked needle. In the event of a blocked needle it should be replaced with a new needle.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially “sodium-free”.
The following substances may reduce insulin requirement: Antidiabetic medicinal products (oral or injectable), salicylates, sulphonamides, certain antidepressants (monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors), angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blocking agents, or somatostatin analogues.
The following substances may increase insulin requirement: oral contraceptives, corticosteroids, thyroid hormones, danazol, sympathomimetic agents, diuretics, or growth hormone.
Alcohol may increase or decrease the blood glucose lowering effect of Lyumjev. Consumption of large amounts of ethanol concomitantly with insulin use may lead to severe hypoglycaemia.
Beta-blockers may blunt the signs and symptoms of hypoglycaemia.
TZDs can cause dose-related fluid retention, particularly when used in combination with insulin, and exacerbate heart failure (see section 4.4).
A large amount of data on pregnant women (more than 1000 pregnancy outcomes) indicate no malformative nor feto/neonatal toxicity of insulin lispro. Lyumjev can be used during pregnancy if clinically needed.
It is essential to maintain good control of an insulin-treated (insulin-dependent or gestational) diabetes patient throughout pregnancy. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. After delivery, insulin requirements normally return rapidly to pre-pregnancy values. Patients with diabetes should be advised to inform their doctor if they are pregnant or are contemplating pregnancy. Careful monitoring of glucose control is essential in pregnant patients with diabetes.
Lyumjev can be used during breast-feeding. Patients with diabetes who are breast-feeding may require adjustments in insulin dose, diet or both.
Insulin lispro did not induce fertility impairment in animal studies.
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 machinery).
Patients should be advised to take precautions to avoid hypoglycaemia whilst driving, this is particularly important in those patients 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 treatment is hypoglycaemia (very common) (see sections 4.2, 4.4 and 4.9).
The following related adverse reactions from clinical trials are listed below as MedDRA preferred term by system organ class and in order of decreasing incidence (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 1. Adverse reactions:
Hypoglycaemia
Lipodystrophy, Rash, Pruritus
Injection site reactions, Allergic reactions*
Oedema
* See section 4.8 Description of selected adverse events
Hypoglycaemia is the most commonly observed adverse reaction in patients using insulin. The incidence of severe hypoglycaemia in the 26 week Phase 3 clinical studies was 5.5 % in patients with type 1 diabetes mellitus and 0.9 % in patients with type 2 diabetes (see tables 2 and 3).
The symptoms of hypoglycaemia usually occur suddenly. They may include listlessness, confusion, palpitations, sweating, vomiting, and headache.
There were no clinically significant differences in the frequency of hypoglycaemia with administration of Lyumjev or the comparator (another medicinal product containing insulin lispro) across all studies. In studies where Lyumjev and the comparator were administered at different times relative to meals, there were no clinically relevant differences in the frequency of hypoglycaemia.
Hypoglycaemia may occur earlier after an injection/infusion of Lyumjev compared to other mealtime insulins due to the earlier onset of action.
Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including Lyumjev.
As with other insulin therapy, patients may experience rash, redness, inflammation, pain, bruising or itching at the site of Lyumjev injection. These reactions are usually mild and usually disappear during continued treatment.
Administration of insulin can cause formation of insulin antibodies. The presence of anti-drug antibodies did not have a clinically meaningful effect on the pharmacokinetics, efficacy, or safety of Lyumjev.
Administration of insulin, including Lyumjev, may result in lipodystrophy [lipohypertrophy (enlargement or thickening of tissue), lipoatrophy (depression in the skin)] or cutaneous amyloidosis (lumps under the skin). Continuous rotation of the injection site within the particular injection area may help to reduce the risk of developing these reactions.
Cases of oedema have been reported with insulin therapy, particularly if previous poor metabolic control is improved by intensified insulin therapy.
Based on results from clinical trials with insulin lispro in general, 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. The safety information in very elderly patients (≥75 years) or patients with moderate to severe renal impairment or hepatic impairment is limited (see section 5.1).
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 any other insulin or any other medicinal product except those mentioned in section 6.6.
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