SULIQUA Solution for injection Ref.[51472] Active ingredients: Insulin glargine Insulin glargine and Lixisenatide Lixisenatide

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Type 1 diabetes mellitus

Suliqua should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Rotation of the injection site

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 medicinal product may be considered.

Hypoglycaemia

Hypoglycaemia was the most frequently reported observed adverse reaction during treatment with Suliqua (see section 4.8). Hypoglycaemia may occur if the dose of Suliqua is higher than required.

Factors increasing the susceptibility to hypoglycaemia require particularly close monitoring and may necessitate dose adjustment. These factors include:

• change in the injection area
• improved insulin sensitivity (e.g., by removal of stress factors)
• unaccustomed, increased or prolonged physical activity
• intercurrent illness (e.g., vomiting, diarrhoea)
• inadequate food intake
• missed meals
• alcohol consumption
• certain uncompensated endocrine disorders, (e.g., in hypothyroidism and in anterior pituitary or adrenocortical insufficiency)
• concomitant treatment with certain other medicinal products (see section 4.5).
• lixisenatide and/or insulin in combination with a sulfonylurea may result in an increased risk of hypoglycaemia. Therefore, Suliqua should not be given in combination with a sulfonylurea.

The dose of Suliqua must be individualised based on clinical response and is titrated based on the patient’s need for insulin (see section 4.2).

Acute pancreatitis

Use of GLP-1 receptor agonists has been associated with a risk of developing acute pancreatitis. There have been few reported events of acute pancreatitis with lixisenatide although a causal relationship has not been established. Patients should be informed of the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, Suliqua should be discontinued; if acute pancreatitis is confirmed, lixisenatide should not be restarted. Caution should be exercised in patients with a history of pancreatitis.

Severe gastrointestinal disease

Use of GLP-1 receptor agonists may be associated with gastrointestinal adverse reactions (see section 4.8). Suliqua has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis and therefore, the use of Suliqua is not recommended in these patients.

Severe renal impairment

There is no therapeutic experience in patients with severe renal impairment (creatinine clearance less than 30 ml/min) or end-stage renal disease. Use is not recommended in patients with severe renal impairment or end-stage renal disease (see sections 4.2 and 5.2).

Concomitant medicinal products

The delay of gastric emptying with lixisenatide may reduce the rate of absorption of orally administered medicinal products. Suliqua should be used with caution in patients receiving oral medicinal products that require rapid gastrointestinal absorption, require careful clinical monitoring or have a narrow therapeutic ratio. Specific recommendations regarding intake of such medicinal products are given in section 4.5.

Dehydration

Patients treated with Suliqua should be advised of the potential risk of dehydration in relation to gastrointestinal adverse reactions and take precautions to avoid fluid depletion.

Antibody formation

Administration of Suliqua may cause formation of antibodies against insulin glargine and/or lixisenatide. In rare cases, the presence of such antibodies may necessitate adjustment of the Suliqua dose in order to correct a tendency for hyperglycaemia or hypoglycaemia.

Avoidance of medication errors

Patients must be instructed to always check the pen label before each injection to avoid accidental mix-ups between the two different strengths of Suliqua and mix-ups with other injectable diabetes medicinal products. To avoid dosing errors and potential overdose, neither the patients nor healthcare professionals should ever use a syringe to draw the medicinal product from the cartridge in the pre-filled pen into a syringe.

Antidiabetic medicinal products not studied in combination with Suliqua

Suliqua has not been studied in combination with dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, glinides, and pioglitazone.

Travel

To avoid dosing errors and potential overdoses with changing to different time zones, the patient should seek the doctor’s advice before travelling.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

This medicinal product contains metacresol, which may cause allergic reactions.

No interaction studies with Suliqua have been performed. The information given below is based on studies with the monocomponents.

Pharmacodynamic interactions

A number of substances affect glucose metabolism and may require dose adjustment of Suliqua.

Substances that may enhance the blood-glucose-lowering effect and increase susceptibility to hypoglycaemia include anti-hyperglycaemic medicinal products, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, pentoxifylline, propoxyphene, salicylates and sulphonamide antibiotics.

Substances that may reduce the blood-glucose-lowering effect include corticosteroids, danazol, diazoxide, diuretics, glucagon, isoniazid, oestrogens and progestogens, phenothiazine derivatives, somatropin, sympathomimetic medicinal products (e.g., epinephrine [adrenaline], salbutamol, terbutaline), thyroid hormones, atypical antipsychotic medicinal products (e.g., clozapine and olanzapine) and protease inhibitors.

Beta-blockers, clonidine, lithium salts or alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycaemia, which may sometimes be followed by hyperglycaemia.

In addition, under the influence of sympatholytic medicinal products such as beta-blockers, clonidine, guanethidine and reserpine, the signs of adrenergic counter-regulation may be reduced or absent.

Pharmacokinetic interactions

Lixisenatide is a peptide and is not metabolised by cytochrome P450. In in vitro studies, lixisenatide did not affect the activity of cytochrome P450 isozymes or human transporters tested. No pharmacokinetic interactions are known for insulin glargine.

Effect of gastric emptying on oral medicinal products

The delay of gastric emptying with lixisenatide may reduce the rate of absorption of orally administered medicinal products. Patients receiving medicinal products of either a narrow therapeutic ratio or medicinal products that require careful clinical monitoring should be followed closely, especially at the time of initiation of lixisenatide treatment. These medicinal products should be taken in a standardised way in relation to lixisenatide. If such medicinal products are to be administered with food, patients should be advised to, if possible, take them with a meal when lixisenatide is not administered.

For oral medicinal products that are particularly dependent on threshold concentrations for efficacy, such as antibiotics, patients should be advised to take those medicinal products at least 1 hour before or 4 hours after lixisenatide injection.

Gastro-resistant formulations containing substances sensitive to stomach degradation, should be administered 1 hour before or 4 hours after lixisenatide injection.

Paracetamol

Paracetamol was used as a model medicinal product to evaluate the effect of lixisenatide on gastric emptying. Following administration of a single dose of paracetamol 1000 mg, paracetamol AUC and t_1/2 were unchanged whatever the timing of its administration (before or after the lixisenatide injection). When administered 1 or 4 hours after 10 mcg lixisenatide, C_max of paracetamol was decreased by 29% and 31%, respectively and median tmax was delayed by 2.0 and 1.75 hours, respectively. A further delay in tmax and a reduced C_max of paracetamol have been predicted with the 20 mcg maintenance dose.

No effects on paracetamol C_max and tmax were observed when paracetamol was administered 1 hour before lixisenatide.

Based on these results, no dose adjustment for paracetamol is required but the delayed tmax observed when paracetamol is administered 1-4 hours after lixisenatide should be taken into account when a rapid onset of action is required for efficacy.

Oral contraceptives

Following administration of a single dose of an oral contraceptive medicinal product (ethinylestradiol 0.03 mg/levonorgestrel 0.15 mg) 1 hour before or 11 hours after 10 mcg lixisenatide, the C_max, AUC, t_1/2 and tmax of ethinylestradiol and levonorgestrel were unchanged.

Administration of the oral contraceptive 1 hour before or 4 hours after lixisenatide did not affect AUC and t_1/2 of ethinylestradiol and levonorgestrel, whereas C_max of ethinylestradiol was decreased by 52% and 39%, respectively and C_max of levonorgestrel was decreased by 46% and 20%, respectively and median tmax was delayed by 1 to 3 hours. The reduction in C_max is of limited clinical relevance and no dose adjustment for oral contraceptives is required.

Atorvastatin

When lixisenatide 20 mcg and atorvastatin 40 mg were co-administered in the morning for 6 days, the exposure to atorvastatin was not affected, while C_max was decreased by 31% and tmax was delayed by 3.25 hours.

No such increase for tmax was observed when atorvastatin was administered in the evening and lixisenatide in the morning but the AUC and C_max of atorvastatin were increased by 27% and 66%, respectively.

These changes are not clinically relevant and, therefore, no dose adjustment for atorvastatin is required when co-administered with lixisenatide.

Warfarin and other coumarin derivatives

After concomitant administration of warfarin 25 mg with repeated dosing of lixisenatide 20 mcg, there were no effects on AUC or INR (International Normalised Ratio) while C_max was reduced by 19% and tmax was delayed by 7 hours.

Based on these results, no dose adjustment for warfarin is required when co-administered with lixisenatide; however, frequent monitoring of INR in patients on warfarin and/or coumarin derivatives is recommended at the time of initiation or ending of lixisenatide treatment.

Digoxin

After concomitant administration of lixisenatide 20 mcg and digoxin 0.25 mg at steady state, the AUC of digoxin was not affected. The tmax of digoxin was delayed by 1.5 hour and the C_max was reduced by 26%.

Based on these results, no dose adjustment for digoxin is required when co-administered with lixisenatide.

Ramipril

After concomitant administration of lixisenatide 20 mcg and ramipril 5 mg during 6 days, the AUC of ramipril was increased by 21% while the C_max was decreased by 63%. The AUC and C_max of the active metabolite (ramiprilat) were not affected. The tmax of ramipril and ramiprilat were delayed by approximately 2.5 hours.

Based on these results, no dose adjustment for ramipril is required when co-administered with lixisenatide.

Women of childbearing potential

Suliqua is not recommended in women of childbearing potential not using contraception.

Pregnancy

There is no clinical data on exposed pregnancies from controlled clinical studies with use of Suliqua, insulin glargine, or lixisenatide.

A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) with insulin glargine indicate no malformative nor feto/neonatal toxicity of insulin glargine. Animal data do not indicate reproductive toxicity with insulin glargine.

There are no or limited amount of data from the use of lixisenatide in pregnant women. Studies with lixisenatide in animals have shown reproductive toxicity (see section 5.3).

Suliqua is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether insulin glargine or lixisenatide are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Suliqua.

Fertility

Animal studies with lixisenatide or insulin glargine do not indicate direct harmful effects with respect to fertility.

Suliqua has no or negligible influence on the ability to drive or use machines. However, 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 should be advised to take precautions to avoid hypoglycaemia while driving and using machines. This is particularly important in those who have reduced or absent awareness of the warning symptoms of hypoglycaemia or have frequent episodes of hypoglycaemia. It should be considered whether it is advisable to drive or use machines in these circumstances.

Summary of the safety profile

The most frequently reported adverse reactions during treatment with Suliqua were hypoglycaemia and gastrointestinal adverse reactions (see section ‘Description of selected adverse reactions’ below).

Tabulated list of adverse reactions

The following related adverse reactions from clinical investigations are listed below by system organ class and in order of decreasing frequency (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; not known: cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse drug reactions reported:

Description of selected adverse reactions

Hypoglycaemia

The following table describes the rate of documented symptomatic hypoglycaemia (≤3.9 mmol/L) and severe hypoglycaemia for both Suliqua and the comparator***.

Table 2. Documented symptomatic or severe hypoglycaemic adverse reactions:

^* Documented symptomatic hypoglycaemia was an event during which typical symptoms of hypoglycaemia were accompanied by a measured plasma glucose concentration of ≤3.9 mmol/L.
^** Severe symptomatic hypoglycaemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
^*** Liraglutide, exenatide BID (twice in a day) or extended release, dulaglutide or albiglutide

Gastrointestinal disorders

Gastrointestinal adverse reactions (nausea, vomiting and diarrhoea) were frequently reported adverse reactions during the treatment period. In patients treated with Suliqua, the incidence of related nausea, diarrhoea and vomiting was 8.4%, 2.2% and 2.2%, respectively. Gastrointestinal adverse reactions were mostly mild and transient in nature.

Immune system disorders

Allergic reactions (urticaria) possibly related with Suliqua have been reported in 0.3% of patients. Cases of generalised allergic reaction including anaphylactic reaction and angioedema have been reported during marketed use of insulin glargine and lixisenatide.

Immunogenicity

Administration of Suliqua may cause formation of antibodies against insulin glargine and/or lixisenatide.

The incidence of formation of anti-insulin glargine antibodies was 21% and 26.2%. In approximately 93% of the patients, anti-insulin glargine antibodies showed cross-reactivity to human insulin. The incidence of formation of anti-lixisenatide antibodies was approximately 43%. Neither status for antiinsulin glargine antibodies nor for anti-lixisenatide antibodies had a clinically relevant impact on safety or efficacy.

Skin and subcutaneous tissue disorders

Lipodystrophy and cutaneous amyloidosis may occur at the injection site of insulins 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).

Injection site reactions

Some (1.7%) patients using insulin containing therapy, including Suliqua have experienced erythema, local oedema, and pruritus at the site of injection.

Heart rate

Increase in heart rate has been reported with GLP-1 receptor agonist use and a transient increase was also observed in some studies with lixisenatide. No increase in mean heart rate was seen in all phase 3 studies with Suliqua.

Reporting of suspected adverse reactions

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.