Lyumjev U200 200 units/mL Solution for injection

LYUMJEV is indicated for the treatment of diabetes mellitus in adults.

Posology
LYUMJEV is a mealtime insulin for subcutaneous injection and should be administered zero to two minutes before the start of the meal, with the option to administer up to 20 minutes after starting the meal (see section 5.1). The initial dosage should take into account the type of diabetes, weight of the patient and their blood glucose levels. The early onset of action must be considered when prescribing LYUMJEV (see section 5.1). Continued adjustment of the dose of LYUMJEV should be based on the patientu2019s metabolic needs, blood glucose monitoring results, and glycaemic control goal. Dose adjustments may be needed, when switching from another insulin, with changes in physical activity, changes in concomitant medicines, changes in meal patterns (i.e., amount and type of food, timing of food intake), changes in renal or hepatic function or during acute illness to minimize the risk of hypoglycaemia or hyperglycaemia (see sections 4.4 and 4.5).

Switching from another mealtime insulin medicine
If converting from another mealtime insulin to LYUMJEV, the change can be done on a unit-to-unit basis. The potency of insulin analogues, including LYUMJEV, is expressed in units. One (1) unit of LYUMJEV corresponds to 1 international unit (IU) of human insulin or 1 unit of other fast-acting insulin analogues.

Missed doses
Patients who forget a mealtime dose should monitor their blood glucose level to decide if an insulin dose is needed, and to resume their usual dosing schedule at the next meal.

Special populations
Elderly (u2265 65 years old)
The safety and efficacy of LYUMJEV has been established in elderly patients aged 65 to 75 years. Close glucose monitoring is recommended and the insulin dose should be adjusted on an individual basis (see sections 4.8, 5.1 and 5.2). The therapeutic experience in patients u2265 75 years of age is limited.

Renal impairment
Insulin requirements may be reduced in the presence of renal impairment. In patients with renal impairment, glucose monitoring should be intensified and the dose adjusted on an individual basis.

Hepatic impairment
Insulin requirements may be reduced in patients with hepatic impairment due to reduced capacity for gluconeogenesis and reduced insulin breakdown. In patients with hepatic impairment, glucose monitoring should be intensified and the dose adjusted on an individual basis.

Paediatric population
The safety and efficacy of LYUMJEV in children and adolescents below 18 years of age have not yet been established. Currently available data are described in section 5.2, but no recommendation on a posology can be made.

Method of administration
Patients should be trained on proper use and injection technique before initiating LYUMJEV. Patients should be told to:

• Always check insulin labels before administration.
• Inspect LYUMJEV visually before use and discard for particulate matter or discolouration.
• Injection sites should always be rotated within the same region in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8).
• Ensure when injecting that a blood vessel has not been entered.
• Discard the needle after each injection.
• Discard devices if any part looks broken or damaged.
• Carry a spare or alternative administration method in case their delivery system breaks.

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

Hypoglycaemia
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.

Hyperglycaemia
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.

Injection technique
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, and dose adjustment of antidiabetic medications may be considered.

Insulin requirements and dose adjustments
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.

Thiazolidinediones (TZDs) used in combination with insulin
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.

Hypersensitivity and allergic reactions
Severe, life-threatening, generalised allergy, including anaphylaxis, can occur with insulin medicines, including LYUMJEV. If hypersensitivity reactions occur, discontinue LYUMJEV.

Medication errors
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. Do not transfer insulin from the LYUMJEV Pen to a syringe. The markings on the insulin syringe will not measure the dose correctly and can result in overdose and severe hypoglycaemia. 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.

Excipients
This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially u201csodium-freeu201d.

The following substances may reduce insulin requirement: Antidiabetic medicines (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).

Pregnancy
A large amount of data on pregnant women (more than 1 000 pregnancy outcomes) indicates 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.

Breastfeeding
LYUMJEV can be used during breastfeeding. Patients with diabetes who are breastfeeding may require adjustments in insulin dose, diet or both.

Fertility
Insulin lispro did not induce fertility impairment in animal studies.

The patientu2019s 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.

Summary of safety profile
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: u2265 1/10; common: u2265 1/100 to < 1/10; uncommon: u2265 1/1 000 to < 1/100; rare: u2265 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
MedDRA System Organ Class
Very common
Common
Uncommon
Not known
Metabolism and nutrition disorders
Hypoglycaemia
Skin and subcutaneous tissue disorders
Lipodystrophy
Rash
Pruritus
Cutaneous amyloidosis
General disorders and administration site conditions
Injection site reactions
Allergic reactions
Oedema
See section 4.8 Description of selected adverse events
Description of selected adverse reactions
Hypoglycaemia
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 medicine 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 of LYUMJEV compared to other mealtime insulins due to the earlier onset of action.

Allergic reactions
Severe, life-threatening, generalised allergy, including anaphylaxis, generalised skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LYUMJEV.

Injection site reactions
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.

Immunogenicity
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.

Skin and subcutaneous tissue disorders
Lipodystrophy 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).

Oedema
Cases of oedema have been reported with insulin therapy, particularly if previous poor metabolic control is improved by intensified insulin therapy.

Special populations
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 (u2265 75 years) or patients with moderate to severe renal impairment or hepatic impairment is limited (see section 5.1).

Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. Alternately, report suspected adverse events to the company at [email protected].

Overdose causes hypoglycaemia with accompanying symptoms that include listlessness, confusion, palpitations, sweating, vomiting, and headache. Hypoglycaemia may occur as a result of an excess of insulin lispro relative to food intake, energy expenditure, or both. Mild episodes of hypoglycaemia usually can be treated with oral glucose. More severe episodes with coma, seizure, or neurologic impairment may be treated with glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycaemia may recur after apparent clinical recovery. Adjustments in medicine dosage, meal patterns, or exercise may be needed.