Insulin Glulisine

Insulin glulisine is a recombinant human insulin analogue made in Escherichia coli. It is equipotent to regular human insulin (one unit has the same glucose-lowering activity as one unit of regular human insulin), but its onset of action is more rapid and its duration shorter, which is why it is used to cover meals.

Mechanism of Action

• Insulin receptor: insulin glulisine binds to the alpha subunits of the insulin receptor, which switches on the tyrosine kinase of the receptor’s beta subunits. The receptor then phosphorylates intracellular substrates (such as the insulin receptor substrate proteins) and activates signalling through PI3 kinase and Akt, which regulates the glucose transporter GLUT4.
• Metabolic effects: like other insulins, it lowers blood glucose by stimulating glucose uptake in peripheral tissues, especially skeletal muscle and fat, and by inhibiting glucose production in the liver. It also inhibits lipolysis in fat cells and proteolysis, and enhances protein synthesis.
• Rapid absorption by design: asparagine at position B3 of the insulin molecule is replaced by lysine, and lysine at position B29 by glutamic acid. These changes reduce the tendency of insulin to form hexamers and keep it in the monomeric form that binds the receptor, giving faster absorption and a shorter action than regular human insulin.
• Time course: after subcutaneous injection, glucose lowering begins within 10–20 minutes. Activity is reported to peak about 60 minutes after injection and to last roughly 2–4 hours. After intravenous administration, onset is faster, duration shorter and the peak response greater than after subcutaneous administration; by this route it is equipotent to regular human insulin.
• Dose proportionality: in 18 men with type 1 diabetes, the glucose-lowering effect was dose-proportional between 0.075 and 0.15 Units/kg and less than proportional from 0.3 Units/kg upwards, as with human insulin.

Pharmacokinetics

• Absorption: about twice as fast as regular human insulin, with a peak concentration about twice as high. In type 1 diabetes, after 0.15 Units/kg subcutaneously, the time to peak was 55 minutes (82 minutes for regular human insulin) and the peak concentration 82 μUnits/mL (46 μUnits/mL for regular human insulin); mean residence time was 98 minutes against 161 minutes. In type 2 diabetes, 0.2 Units/kg gave a peak of 91 μUnits/mL.
• Injection site and bioavailability: profiles are similar after injection into the abdomen, deltoid or thigh, with slightly faster absorption from the abdomen. Absolute bioavailability is about 70% at all sites, with low variability within a patient (11%). An intravenous bolus gives a peak concentration about 40 times higher than a subcutaneous dose.
• Body weight: rapid absorption and total exposure are largely maintained across body mass indices of 18–46 kg/m².
• Distribution: after intravenous dosing, the volume of distribution is about 13 L (22 L for regular human insulin). Plasma protein binding is low, similar to human insulin.
• Elimination: after intravenous dosing, the half-life is 13 minutes (18 minutes for regular human insulin). After subcutaneous dosing, the apparent half-life is 42 minutes against 86 minutes for regular human insulin (37–75 minutes across studies).
• Special populations: in renal impairment (creatinine clearance above 80, 30–50 and below 30 mL/min) the rapid-acting properties are generally maintained, although insulin requirements may fall. Pharmacokinetics have not been studied in hepatic impairment, and data in elderly patients are very limited. In children (7–11 years) and adolescents (12–16 years) with type 1 diabetes, absorption was rapid, with peak time and concentration similar to adults.

• Diabetes mellitus: treatment of adults, adolescents and children aged 6 years or older with diabetes mellitus, where treatment with insulin is required.
• Use with other treatment (SmPC section 4.2): Apidra is used in regimens that include an intermediate- or long-acting insulin or a basal insulin analogue, and can be combined with oral antidiabetic medicines.

• Hypersensitivity to insulin glulisine or to any of the excipients.
• Hypoglycaemia.

Hypoglycaemia, the most frequent adverse reaction of insulin therapy, may occur if the insulin dose is too high in relation to the insulin requirement.

Very common (≥1/10): hypoglycaemia (metabolism and nutrition disorders).

Common (≥1/100 to <1/10): injection site reactions and local hypersensitivity reactions (skin and subcutaneous tissue disorders).

Uncommon (≥1/1,000 to <1/100): systemic hypersensitivity reactions (general disorders and administration site conditions).

Rare (≥1/10,000 to <1/1,000): lipodystrophy (skin and subcutaneous tissue disorders).

Not known: hyperglycaemia, potentially leading to diabetic ketoacidosis (metabolism and nutrition disorders; with the vial, most cases were related to handling errors or pump failure during continuous subcutaneous infusion); cutaneous amyloidosis (skin and subcutaneous tissue disorders).

Symptoms of hypoglycaemia usually come on suddenly and may include cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiousness, unusual tiredness or weakness, confusion, difficulty concentrating, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation. Severe hypoglycaemia can lead to unconsciousness or convulsions and to temporary or permanent impairment of brain function, or even death.

No pharmacokinetic interaction studies have been performed, and clinically relevant pharmacokinetic interactions are unlikely. Many substances, however, affect glucose metabolism and may call for a dose adjustment of insulin glulisine and particularly close monitoring.

• May increase the glucose-lowering effect and the risk of hypoglycaemia: oral antidiabetic medicines, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, propoxyphene, salicylates and sulphonamide antibiotics.
• May reduce the glucose-lowering effect: corticosteroids, danazol, diazoxide, diuretics, glucagon, isoniazid, phenothiazine derivatives, somatropin, sympathomimetic medicines (such as adrenaline, salbutamol and terbutaline), thyroid hormones, oestrogens, progestogens (for example in oral contraceptives), protease inhibitors and atypical antipsychotics (such as olanzapine and clozapine).
• May either increase or reduce the effect: beta-blockers, clonidine, lithium salts and alcohol. Pentamidine can cause hypoglycaemia, sometimes followed by hyperglycaemia. Alcohol may also impair blood glucose control and should be avoided.
• Masked warning signs: sympatholytic medicines such as beta-blockers, clonidine, guanethidine and reserpine may reduce or abolish the signs of adrenergic counter-regulation that warn of hypoglycaemia.
• Pioglitazone: cardiac failure has been reported when it is combined with insulin (see Special Instructions).

The dose of Apidra is adjusted individually by the treating doctor. Apidra is given within a regimen that includes an intermediate- or long-acting insulin or a basal insulin analogue, and can be used with oral antidiabetic medicines. Its potency is stated in Units that are exclusive to Apidra; they are not the same as IU or as the units used for other insulin analogues.

Dose and Timing

• Subcutaneous injection: shortly (0–15 minutes) before a meal or soon after a meal, or by continuous subcutaneous pump infusion.
• Injection sites: abdominal wall, thigh or deltoid; for continuous infusion, the abdominal wall. Sites within an area (abdomen, thigh or deltoid) must be rotated from one injection to the next to reduce the risk of lipodystrophy and cutaneous amyloidosis.
• Absorption: the rate of absorption, and so the onset and duration of action, can be affected by the injection site, exercise and other variables. Injection into the abdominal wall gives slightly faster absorption than other sites.
• Technique: take care not to enter a blood vessel; do not massage the site after injection; patients must be taught proper injection technique.
• Mixing: when injected subcutaneously, Apidra must not be mixed with other medicinal products except NPH human insulin.

Presentations and Routes

• Vial: for subcutaneous injection with a syringe. It can also be given intravenously, which healthcare professionals must carry out; it must not be mixed with glucose, Ringer’s solution or any other insulin.
• Continuous subcutaneous infusion (vial): in pump systems suitable for insulin infusion, with appropriate catheters and reservoirs. Patients need thorough training on the pump. The infusion set and reservoir must be changed at least every 48 hours with aseptic technique, following the Apidra-specific instructions, which may differ from the pump manual. Apidra must not be mixed with diluents or any other insulin in the pump, and the patient needs an alternative way to give insulin in case the pump fails.
• Cartridge: only for subcutaneous injection from a reusable pen. It may be used only with the pens named in the SmPC (JuniorSTAR, which delivers 0.5 Unit steps, and ClikSTAR, Tactipen, Autopen 24, AllStar and AllStar PRO, which deliver 1 Unit steps; not all are marketed in every country), because dosing accuracy is established only for them.
• SoloStar pre-filled pen: only for subcutaneous injection. The instructions for use in the package leaflet must be read before use.
• Syringe, intravenous or pump use: if any of these is necessary, a vial must be used; the cartridge and the pre-filled pen are not suitable.

Dose Adjustments and Changing Insulin

• Dose adjustment may be needed with more physical activity or a changed meal plan. Exercise immediately after a meal may increase the risk of hypoglycaemia. Insulin requirements may change during illness or emotional disturbance.
• Transfer to another type or brand of insulin must be done under strict medical supervision. Changes in strength, brand (manufacturer), type (regular, NPH, lente, long-acting), origin (animal, human, analogue) or method of manufacture can require a dose change, and concomitant oral antidiabetic treatment may need adjusting.
• After a sudden change of injection site to an unaffected area, blood glucose monitoring is recommended and adjustment of antidiabetic medicines may be considered.

Special Populations

• Renal impairment: pharmacokinetic properties are generally maintained, but insulin requirements may be reduced.
• Hepatic impairment: not investigated; requirements may be diminished because of reduced capacity for gluconeogenesis and reduced insulin metabolism.
• Elderly: limited pharmacokinetic data; deterioration of renal function may lead to lower insulin requirements.
• Children and adolescents: authorised from 6 years of age. There is insufficient clinical information for children younger than 6 years.

Traceability and Changing Insulin

The name and batch number of the administered product should be clearly recorded. Any transfer to another insulin must be supervised closely by a doctor (see Administration and Dosage).

Hypoglycaemia

The time at which hypoglycaemia occurs depends on the action profile of the insulins used and may change when the regimen is changed. Warning symptoms may be different or less pronounced with long-standing diabetes, intensified insulin therapy, diabetic nerve disease, medicines such as beta-blockers, or after transfer from animal-source to human insulin. Compared with soluble human insulin, hypoglycaemia after a rapid-acting analogue may occur earlier. Uncorrected hypoglycaemic or hyperglycaemic reactions can cause loss of consciousness, coma or death.

Hyperglycaemia and Ketoacidosis

Inadequate doses or stopping treatment, especially in insulin-dependent diabetes, may lead to hyperglycaemia and diabetic ketoacidosis, which are potentially lethal.

Injection Site Changes

Continuous rotation of injection sites reduces the risk of lipodystrophy and cutaneous amyloidosis. Injecting into sites with these reactions may delay insulin absorption and worsen glycaemic control, and a sudden move to an unaffected site has been reported to cause hypoglycaemia.

Insulin Pump Use (Vial)

A malfunction of the pump or infusion set, or a handling error, can rapidly lead to hyperglycaemia, ketosis and diabetic ketoacidosis. The cause must be found and corrected promptly. Interim subcutaneous injections may be needed, so patients on pump therapy must be trained to inject insulin and have an alternative delivery system available.

Medication Errors

Other insulins, particularly long-acting insulins, have been given by accident instead of insulin glulisine. The insulin label must be checked before every injection.

Combination with Pioglitazone

Cardiac failure has been reported when pioglitazone is combined with insulin, especially in patients with risk factors for heart failure. Patients on the combination should be watched for signs and symptoms of heart failure, weight gain and oedema, and pioglitazone should be stopped if cardiac symptoms worsen.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: fewer than 300 pregnancy outcomes are available. Animal studies showed no differences between insulin glulisine and human insulin for pregnancy, embryonal or foetal development, birth or postnatal development. Caution is needed when prescribing in pregnancy, and careful monitoring of glucose control is essential. Good metabolic control must be kept throughout pregnancy. Insulin requirements may fall in the first trimester, generally rise in the second and third, and drop rapidly after delivery.
• Breastfeeding: it is unknown whether insulin glulisine passes into human milk, but insulin in general does not pass into breast milk and is not absorbed after oral intake. Dose and diet may need adjusting.
• Fertility: animal studies showed no adverse effects on fertility.

Excipients

The medicine contains less than 1 mmol (23 mg) of sodium per dose, so it is essentially sodium-free. It contains metacresol, which may cause allergic reactions.

Effect on Driving

The ability to concentrate and react may be impaired by hypoglycaemia or hyperglycaemia, or for example by visual impairment, which is a risk when driving or operating machines. Patients should be advised to take precautions to avoid hypoglycaemia while driving.

Before first use, Apidra vials, cartridges and SoloStar pens are kept in a refrigerator at 2–8 °C. Do not freeze, and do not place next to the freezer compartment or a freezer pack. Keep in the outer carton to protect from light. Cold-chain handling applies to supply and transport.

• Vial in use: up to 4 weeks below 25 °C, away from direct heat or direct light and in the outer carton. The date of first use should be noted on the label.
• Cartridge or SoloStar pen in use: up to 4 weeks below 25 °C, away from direct heat or direct light. A pen in use must not be put in the refrigerator, and the cap is put back on after each injection to protect from light.

2 years (unopened, stored at 2–8 °C). After first use, 4 weeks for the vial, cartridge or pen. For intravenous use at 1 Unit/mL, insulin glulisine is stable between 15 °C and 25 °C for 48 hours (see the SmPC for preparation).

Prescription only (Rx): a medicinal product subject to medical prescription. Pens, cartridges and vials are used by the patient or a carer after training, so they are supplied to the patient or to the treating clinic on prescription, with cold-chain delivery at 2–8 °C. Intravenous use of the vial is carried out by healthcare professionals and is supplied to the hospital or clinic that administers it.