XULTOPHY Solution for injection Ref.[50802] Active ingredients: Insulin degludec Insulin degludec and Liraglutide Liraglutide

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

Hypoglycaemia

Hypoglycaemia may occur if the dose of Xultophy is higher than required. Omission of a meal or unplanned strenuous physical exercise may lead to hypoglycaemia. In combination with sulfonylurea, the risk of hypoglycaemia may be lowered by a reduction in the dose of sulfonylurea. Concomitant diseases in the kidney, liver or diseases affecting the adrenal, pituitary or thyroid gland may require changes of the Xultophy dose. Patients whose blood glucose control is greatly improved (e.g. by intensified therapy) may experience a change in their usual warning symptoms of hypoglycaemia and must be advised accordingly. Usual warning symptoms (see section 4.8) of hypoglycaemia may disappear in patients with long-standing diabetes. The prolonged effect of Xultophy may delay recovery from hypoglycaemia.

Hyperglycaemia

Inadequate dosing and/or discontinuation of antidiabetic treatment may lead to hyperglycaemia and potentially to hyperosmolar coma. In case of discontinuation of Xultophy, ensure that instruction for initiation of alternative antidiabetic treatment is followed. Furthermore, concomitant illness, especially infections, may lead to hyperglycaemia and thereby cause an increased requirement for antidiabetic treatment. 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, and loss of appetite as well as acetone odour of breath.

Administration of rapid-acting insulin should be considered in situations of severe hyperglycaemia. Untreated hyperglycaemic events eventually lead to hyperosmolar coma/diabetic ketoacidosis, which is potentially lethal.

Skin and subcutaneous tissue disorders

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 medications may be considered.

Combination of pioglitazone and insulin medicinal products

Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin medicinal products, especially in patients with risk factors for development of cardiac failure. This should be kept in mind if treatment with the combination of pioglitazone and Xultophy is considered. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.

Eye disorder

Intensification of therapy with insulin, a component of Xultophy, with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy, while longterm improved glycaemic control decreases the risk of progression of diabetic retinopathy.

Antibody formation

Administration of Xultophy may cause formation of antibodies against insulin degludec and/or liraglutide. In rare cases, the presence of such antibodies may necessitate adjustment of the Xultophy dose in order to correct a tendency to hyper- or hypoglycaemia. Very few patients developed insulin degludec specific antibodies, antibodies cross-reacting to human insulin or anti-liraglutide antibodies following treatment with Xultophy. Antibody formation has not been associated with reduced efficacy of Xultophy.

Acute pancreatitis

Acute pancreatitis has been observed with the use of GLP-1 receptor agonists, including liraglutide. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, Xultophy should be discontinued; if acute pancreatitis is confirmed, Xultophy should not be restarted.

Thyroid adverse events

Thyroid adverse events, such as goitre have been reported in clinical trials with GLP-1 receptor agonists including liraglutide, and in particular in patients with pre-existing thyroid disease. Xultophy should therefore be used with caution in these patients.

Inflammatory bowel disease and diabetic gastroparesis

There is no experience with Xultophy in patients with inflammatory bowel disease and diabetic gastroparesis. Xultophy is therefore not recommended in these patients.

Dehydration

Signs and symptoms of dehydration, including renal impairment and acute renal failure have been reported in clinical trials with GLP-1 receptor agonists including liraglutide, a component of Xultophy. Patients treated with Xultophy should be advised of the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion.

Avoidance of medication errors

Patients must be instructed to always check the pen label before each injection to avoid accidental mix-ups between Xultophy and other injectable diabetes medicinal products.

Patients must visually verify the dialled units on the dose counter of the pen. Therefore, the requirement for patients to self-inject is that they can read the dose counter on the 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 insulin device.

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 (see section 6.6).

Populations not studied

Transfer to Xultophy from doses of basal insulin <20 and >50 units has not been studied.

There is no therapeutic experience in patients with congestive heart failure New York Heart Association (NYHA) class IV and Xultophy is therefore not recommended for use in these patients.

Excipients

Xultophy contains less than 1 mmol sodium (23 mg) per dose, therefore the medicinal product is essentially ‘sodium-free’.

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.

Pharmacodynamic interactions

Interaction studies with Xultophy have not been performed. A number of substances affect glucose metabolism and may require dose adjustment of Xultophy.

The following substances may reduce the Xultophy requirement: Antidiabetic medicinal products, monoamine oxidase inhibitors (MAOI), beta-blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulfonamides.

The following substances may increase the Xultophy requirement: Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormones and danazol.

Beta-blockers may mask the symptoms of hypoglycaemia.

Octreotide/lanreotide may either increase or decrease the Xultophy requirement.

Alcohol may intensify or reduce the hypoglycaemic effect of Xultophy.

Pharmacokinetic interactions

In vitro data suggest that the potential for pharmacokinetic drug interactions related to CYP interaction and protein binding is low for both liraglutide and insulin degludec.

The small delay of gastric emptying with liraglutide may influence absorption of concomitantly administered oral medicinal products. Interaction studies did not show any clinically relevant delay of absorption.

Warfarin and other coumarin derivatives

No interaction study has been performed. A clinically relevant interaction with active substances with poor solubility or with narrow therapeutic index such as warfarin cannot be excluded. Upon initiation of Xultophy treatment in patients on warfarin or other coumarin derivatives more frequent monitoring of INR (International Normalised Ratio) is recommended.

Paracetamol

Liraglutide did not change the overall exposure of paracetamol following a single dose of 1,000 mg. Paracetamol C_max was decreased by 31% and median t_max was delayed up to 15 min. No dose adjustment for concomitant use of paracetamol is required.

Atorvastatin

Liraglutide did not change the overall exposure of atorvastatin to a clinical relevant degree following single dose administration of atorvastatin 40 mg. Therefore, no dose adjustment of atorvastatin is required when given with liraglutide. Atorvastatin C_max was decreased by 38% and median t_max was delayed from 1 h to 3 h with liraglutide.

Griseofulvin

Liraglutide did not change the overall exposure of griseofulvin following administration of a single dose of griseofulvin 500 mg. Griseofulvin C_max increased by 37% while median t_max did not change. Dose adjustments of griseofulvin and other compounds with low solubility and high permeability are not required.

Digoxin

A single dose administration of digoxin 1 mg with liraglutide resulted in a reduction of digoxin AUC by 16%; C_max decreased by 31%. Digoxin median time to maximum concentration (t_max) was delayed from 1 h to 1.5 h. No dose adjustment of digoxin is required based on these results.

Lisinopril

A single dose administration of lisinopril 20 mg with liraglutide resulted in a reduction of lisinopril AUC by 15%; C_max decreased by 27%. Lisinopril median t_max was delayed from 6 h to 8 h with liraglutide. No dose adjustment of lisinopril is required based on these results.

Oral contraceptives

Liraglutide lowered ethinylestradiol and levonorgestrel C_max by 12 and 13%, respectively, following administration of a single dose of an oral contraceptive product. T_max was delayed by 1.5 h with liraglutide for both compounds. There was no clinically relevant effect on the overall exposure of either ethinylestradiol or levonorgestrel. The contraceptive effect is therefore anticipated to be unaffected when co-administered with liraglutide.

Pregnancy

There is no clinical experience with the use of Xultophy, insulin degludec or liraglutide in pregnant women. If a patient wishes to become pregnant, or pregnancy occurs, treatment with Xultophy should be discontinued.

Animal reproduction studies with insulin degludec have not revealed any differences between insulin degludec and human insulin regarding embryotoxicity and teratogenicity. Animal studies with liraglutide have shown reproductive toxicity, see section 5.3. The potential risk for humans is unknown.

Breast-feeding

There is no clinical experience with the use of Xultophy during breast-feeding. It is not known whether insulin degludec or liraglutide is excreted in human milk. Because of lack of experience, Xultophy should not be used during breast-feeding.

In rats, insulin degludec was secreted in milk; the concentration in milk was lower than in plasma. Animal studies have shown that the transfer of liraglutide and metabolites of close structural relationship into milk was low. Non-clinical studies with liraglutide have shown a treatment-related reduction of neonatal growth in suckling rat pups (see section 5.3).

Fertility

There is no clinical experience with Xultophy in relation to fertility. Animal reproduction studies with insulin degludec have not revealed any adverse effects on fertility. Apart from a slight decrease in the number of live implants, animal studies with liraglutide did not indicate harmful effects with respect to fertility.

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 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.

Summary of the safety profile

The Xultophy clinical development programme included approximately 1,900 patients treated with Xultophy.

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

Tabulated list of adverse reactions

Adverse reactions associated with Xultophy are given below, listed by system organ class and frequency. Frequency categories are defined as: 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 reported in phase 3 controlled studies:

^† ADR from postmarketing sources.

Description of selected adverse reactions

Hypoglycaemia

Hypoglycaemia may occur if the Xultophy dose is higher than required. 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. For frequencies of hypoglycaemia, please see section 5.1.

Allergic reactions

Allergic reactions (manifested with signs and symptoms such as urticaria (0.3% of patients treated with Xultophy), rash (0.7%), pruritus (0.5%) and/or swelling of the face (0.2%)) have been reported for Xultophy. Few cases of anaphylactic reactions with additional symptoms such as hypotension, palpitations, dyspnoea, and oedema have been reported during marketed use of liraglutide. Anaphylactic reactions may potentially be life threatening.

Gastrointestinal adverse reactions

Gastrointestinal adverse reactions may occur more frequently at the beginning of Xultophy therapy and usually diminish within a few days or weeks on continued treatment. Nausea was reported in 7.8% of patients and was transient in nature for most patients. The proportion of patients reporting nausea per week at any point during treatment was below 4%. Diarrhoea and vomiting were reported in 7.5% and 3.9% of patients, respectively. The frequency of nausea and diarrhoea was ‘Common’ for Xultophy and ‘Very common’ for liraglutide. In addition, constipation, dyspepsia, gastritis, abdominal pain, gastroesophageal reflux disease, abdominal distension, eructation, flatulence and decreased appetite have been reported in up to 3.6% of patients treated with Xultophy.

Injection site reactions

Injection site reactions (including injection site haematoma, pain, haemmorrhage, erythema, nodules, swelling, discolouration, pruritus, warmth and injection site mass) have been reported in 2.6% of patients treated with Xultophy. These reactions were usually mild and transitory and they normally disappear during continued treatment.

Skin and subcutaneous tissue disorders

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).

Increased heart rate

Mean increase in heart rate from baseline of 2 to 3 beats per minute has been observed in clinical trials with Xultophy. In the LEADER trial, no long-term clinical impact of increased heart rate on the risk of cardiovascular events was observed with liraglutide (a component of Xultophy) (see section 5.1).

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.

Substances added to Xultophy may cause degradation of the active substances.

Xultophy must not be added to infusion fluids.

This medicinal product must not be mixed with other medicinal products.