Insulin glargine

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.

In patients with hepatic impairment, insulin requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism.

In patients with renal impairment, insulin requirements may be diminished due to reduced insulin metabolism.

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 sulfonamide antibiotics.

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.

Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. This should be kept in mind if treatment with the combination of pioglitazone and insulin glargine 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.

There is no clinical experience with use of insulin glargine in pregnant women.

For insulin glargine no clinical data on exposed pregnancies from controlled clinical studies are available. A large amount of data on pregnant women (more than 1,000 pregnancy outcomes with a medicinal product containing insulin glargine 100 units/ml) indicate no specific adverse effects on pregnancy and no specific malformative nor feto/neonatal toxicity of insulin glargine. Animal data do not indicate reproductive toxicity. The use of insulin glargine may be considered during pregnancy, if clinically needed.

It is essential for patients with pre-existing or gestational diabetes to maintain good metabolic control throughout pregnancy to prevent adverse outcomes associated with hyperglycaemia. Insulin requirements may decrease during the first trimester and generally increase during the second and third trimesters. Immediately after delivery, insulin requirements decline rapidly (increased risk of hypoglycaemia). Careful monitoring of glucose control is essential.

It is unknown whether insulin glargine is excreted in human milk. No metabolic effects of ingested insulin glargine on the breast-fed newborn/infant are anticipated since insulin glargine as a peptide is digested into aminoacids in the human gastrointestinal tract.

Breast-feeding women may require adjustments in insulin dose and diet.

Fertility

Animal studies do not indicate direct harmful effects with respect to fertility.

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 whilst driving. 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 following adverse reactions were observed during clinical studies conducted with insulin glargine 300 units/ml and during clinical experience with insulin glargine 100 units/ml. Hypoglycaemia, in general the most frequent adverse reaction of insulin therapy, may occur if the insulin dose is too high in relation to the insulin requirement.

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 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; not known: cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Description of selected adverse reactions

Metabolism and nutrition disorders

Severe hypoglycaemic attacks, especially if recurrent, may lead to neurological damage. Prolonged or severe hypoglycaemic episodes may be life-threatening.

In many patients, the signs and symptoms of neuroglycopenia are preceded by signs of adrenergic counter-regulation. Generally, the greater and more rapid the decline in blood glucose, the more marked is the phenomenon of counter-regulation and its symptoms.

Immune system disorders

Immediate-type allergic reactions to insulin are rare. Such reactions to insulin (including insulin glargine) or the excipients may, for example, be associated with generalised skin reactions, angio-oedema, bronchospasm, hypotension and shock, and may be life-threatening. In insulin glargine clinical studies in adult patients, the incidence of allergic reactions was similar in insulin glargine-treated patients (5.3%) and insulin glargine 100 units/ml-treated patients (4.5%).

Eyes disorders

A marked change in glycaemic control may cause temporary visual impairment, due to temporary alteration in the turgidity and refractive index of the lens.

Long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy. However, intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy. In patients with proliferative retinopathy, particularly if not treated with photocoagulation, severe hypoglycaemic episodes may result in transient amaurosis.

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.

General disorders and administration site conditions

Injection site reactions include redness, pain, itching, hives, swelling, or inflammation. Most minor reactions to insulins at the injection site usually resolve in a few days to a few weeks. In insulin glargine clinical studies in adult patients, the incidence of injection site reactions was similar in insulin glargine-treated patients (2.5%) and insulin glargine 100 units/ml-treated patients (2.8%).

Rarely, insulin may cause oedema particularly if previously poor metabolic control is improved by intensified insulin therapy.

Paediatric population

Safety and efficacy of insulin glargine have been demonstrated in a study in children aged 6 to less than 18 years. The frequency, type and severity of adverse reactions in the paediatric population do not indicate differences to the experience in the general diabetes population. Clinical study safety data are not available for children under 6 years.

Other special populations

Based on the results from clinical studies, the safety profile of insulin glargine in elderly patients and in patients with renal impairment was similar to that of the overall population.