Insulin degludec and Liraglutide

When insulin degludec/liraglutide combination is used in patients with mild, moderate or severe renal impairment, glucose monitoring is to be intensified and the dose adjusted on an individual basis. Insulin degludec/liraglutide combination cannot be recommended for use in patients with end-stage renal disease.

Due to the liraglutide component, insulin degludec/liraglutide combination is not recommended for use in patients with severe hepatic impairment.

There is no clinical experience with the use of insulin degludec/liraglutide fixed-dose combination, insulin degludec or liraglutide in pregnant women. If a patient wishes to become pregnant, or pregnancy occurs, treatment with insulin degludec/liraglutide 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. The potential risk for humans is unknown.

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

Fertility

There is no clinical experience with insulin degludec/liraglutide 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 insulin degludec/liraglutide clinical development programme included approximately 1,900 patients treated with insulin degludec/liraglutide.

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

Tabulated list of adverse reactions

Adverse reactions associated with insulin degludec/liraglutide 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).

Adverse reactions reported in phase 3 controlled studies:

^† ADR from postmarketing sources.

Description of selected adverse reactions

Hypoglycaemia

Hypoglycaemia may occur if the insulin degludec/liraglutide 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.

Allergic reactions

Allergic reactions (manifested with signs and symptoms such as urticaria (0.3% of patients treated with insulin degludec/liraglutide), rash (0.7%), pruritus (0.5%) and/or swelling of the face (0.2%)) have been reported for insulin degludec/liraglutide. 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 insulin degludec/liraglutide 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 insulin degludec/liraglutide 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 insulin degludec/liraglutide.

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 insulin degludec/liraglutide. 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.

Increased heart rate

Mean increase in heart rate from baseline of 2 to 3 beats per minute has been observed in clinical trials with insulin degludec/liraglutide. In the LEADER trial, no long-term clinical impact of increased heart rate on the risk of cardiovascular events was observed with liraglutide.