Dosage Form: Injection
Insulin lispro…………..3.5 mg
m-Cresol [3/15 mg/ml], glycerol, dibasic sodium phosphate, 7H2O, zinc oxide, water for injections, Hydrochloric acid and sodium hyrdroxide may be used to adjust pH to 7.0-7.8
Pharmacotherapeutic group: Fast-acting human insulin analogue. ATC code: A10A B04.
The primary activity of insulin lispro is the regulation of glucose metabolism.
In addition, insulins have several anabolic and anticatabolic actions on a variety of different tissues. Within muscle tissue this includes increasing glycogen, fatty acid, gylcerol and protein synthesis and amino acid uptake, while decreasing glycogenoylsis, ketogenesis, lipolysis, protein catabolism and amino acid output.
Insulin lispro has a rapid onset of action (approximately 15 minutes), this allowing it to be given closer to a meal (within zero to 15 minutes of the meal) when compared to regular insulin (30 to 45 minutes before). Insulin lispro takes effect rapidly and has a shorter duration of activity (2 to 5 hours) when compared to regular insulin.
Clinical trials in patients with type 1 and type 2 diabetes have demonstrated reduced postprandial hyperglycaemia with insulin lispro compared to soluble human insulin. For fast-acting insulins, any patient also on a basal insulin must optimize dosage of both insulins to obtain improved glucose control across the whole day.
As with all insulin preparations, the time course of insulin lispro action may vary in different individuals, or at different times in the same individual and is dependent on the dose, site of injections, blood supply, temperature and physical activity. The typical activity profile following subcutaneous injections is illustrated below.
The above representation reflects the relative amount of glucose over time required to maintain the subject’s whole blood glucose concentrations near fasting levels and is an indicator of the effect of these insulins on glucose metabolism over time.
Clinical trials have been performed in children (61 patients aged 2 to 11), and children and adolescents (481 patients aged 9 to 19 years), comparing insulin lispro to human soluble insulin. The pharmacodynamic profile of insulin lispro in children is similar to that seen in adults.
When used in subcutaneous infusion pumps, treatment with insulin lispro has been shown to result in lower glycosylated haemoglobin levels compared to soluble insulin. In a double-blind, crossover study, the reduction in glycosylated haemoglobin levels after 12 weeks dosing was 0.37 percentage points with insulin lispro, compared to 0.03 percentage points for soluble insulin (p=0.004).
In patients with type 2 diabetes on maximum doses of sulphonylurea agents studies have shown that the addition of insulin lispro singificantly reduces HBA1c compared to sulphonylurea alone. The reduction of HB1Ac would also be expected with other insulin products, e.g. soluble or isophane insulins.
Clincial trials in patients with type 1 and type 2 diabetes have demonstrated a reduced number of episodes of nocturnal hypoglycemia with insulin lispro compared to soluble human insulin. In some studies, reduction of nocturnal hypogylcaemia was associated with increased episodes of daytime hypoglycaemia.
The glucodynamic respone to insulin lispro is not affected by renal or hepatic function impairment. Glucodynamic differences between insulin lispro and soluble human insulin, as measured during a glucose clamp procedure, were maintained over a wide range of renal function.
Insulin lispro has been shown to be equipotent to human insulin on a molar basis but its effect is more rapid and of a shorter duration.
The pharmacokinetics of insulin lispro reflect a compound that is rapidly absorbed, and achieves peak blood levels 30 to 70 minutes following subcutaneous injection. When considering the clinical relevance of these kinetics, it is more appropriate to examine the glucose utilisation curves (as discussed in pharmacodynamics).
Insulin lispro maintains more rapid absorption when compared to soluble human insulin in patients with renal impairment. In patients with type 2 diabetes over a wide range of renal function the pharmacokinetic differences between insulin lispro and soluble human insulin were generally maintained and shown to be independent of renal function. Insulin lispo maintains more rapid absorption and elimination when compared to soluble human insulin in patients with hepatic impairment.
Preclinical Safety Data
In in vitro tests, including binding to insulin receptor sites and effects on growing cells, insulin lispro behaved in a manner that closely resembled human insulin. Studies also demonstrate that the dissociation of binding to the insulin receptor of insulin lispro is equivalent to human insulin. Acute, one month and twelve month toxicology studies produced no significant toxicity findings.
Insulin lispro did not induce fertility impairment, embryotoxicity or teratogenicity in animal studies.
For the treatment of adults and children with diabetes mellitus who require insulin for the maintenance of normal glucose homeostasis. Humalog is also indicated for the initial stabilization of diabetes mellitus.
Use of Humalog is contraindicated in:
- Hypersensitivity to insulin lispro or to any of the excipients
- Humalog preparations should not be mixed with insulin produced by other manufacturers or with animal insulin preparations
Insulin requirements may be increased medicinal products with hyperglycemic activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy, danazol, beta-2-stimulants (such as ritodrine, salbutamol, terbutaline).
Insulin requirements may be reduced in the presence of medicinal products with hypoglycemic activity, such as oral hypogylcemics, salicylates (for example, acetylsalicylic acid), sulpha antibiotics, certain antidepressants (monoamine oxidase inhibitors), certain angiotensin converting enzyme inhibitors (captopril, enalapril), beta-blockers, octreotide or alcohol.
The physician should be consulted when using other medications in addition to Humalog.
Hypogylcemia is the most frequent undesirable effects of insulin therapy that a patient with diabetes may suffer. Severe hypoglycemia may lead to loss of consciousness, and in extreme cases, death.
Local allergy in patient occasionally occurs as redness, swelling, and itching at the site of insulin injection. This condition usually resolves in a few days to a few weeks. In some instances, this condition may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique. Systemic allergy, less common but potential more serious, is a generalized allergy to insulin. It may cause rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life-threatening.
Lipodystrophy may occur at the injection site.
Dosage and Administration:
1. Posology and Method of Administration:
The dosage should be determined by the physician, according to the requirement of the patient.
Humalog may be given shortly after meals. When necessary, Humalog can be given soon after meals Humalog preparations should be given by subcutaneous injection or by continuous subcutaneous infusion pump (see section 6.6d) and may, although not recommended, also be given by intramuscular injection. If necessary, Humalog may also be administered intravenously, for example; for the control of blood glucose levels during ketoacidosis, acute illnesses or during intra- and post-operative periods.
Subcutaneous administration should be in the upper arms, thighs, buttocks, or abdomen. Use of injection sites should be rotated so that the same site is not used more than approximately once a month.
When administered subcutaneously, care should be taken when injecting Humalog to ensure that a blood vessel has not been entered. After injection, the site of injection should not be massaged. Patients must be educated to use the proper injection techniques.
Humalog takes effect rapidly and has a shorter duration of activity (2 to 5 hours) given subcutaneously as compared with regular insulin. This rapid onset of activity allows a Humalog injection (or, in the case of administration by continuous subcutaneous infusion, a Humalog bolus) to be given very close to mealtime. The time course of action of any insulin may vary considerably in different individuals or at different times in the same individual. The faster onset of action compared to soluble human insulin is maintained regardless of injection site. As with all insulin preparations, the duration of action of Humalog is dependent on dose, site of injection, blood supply, temperature, and physical activity.
Humalog can be used in conjunction with a longer-acting human insulin or oral sulphonylurea agents, on the advice of a physician.
2. Instructions for Use, Handling and Disposal:
Humalog cartridges are to be used with a CE marked pen, as recommended in the information provided by the device manufacturer.
a) Preparing a dose:
Inspect the Humalog solution. It should be clear and colorless. Do not use Humalog if it appears cloudy, thickened, or slightly colored or if solid particles are visible.
The following is a general description. The manufacturer’s instructions with each individual pen must be followed for loading the cartridge, attaching the needle and administering the insulin injection.
b) Injecting a dose:
- Wash your hands
- Choose a site for injection
- Clean the skin as instructed
- Remove outer needle cap
- Stabilize the skin by spreading it or pinching up a large area
- Insert the needle as instructed
- Press the knob
- Pull the needle out and apply gentle pressure over the injection site for several seconds. Do not rub the area.
- Using the outer needle cap, unscrew the needle and dispose it safely.
- Use of injection sites should be rotated so that the same site is not used more than approximately once a month
c) Mixing Insulins:
Do not mix insulin in vials with insulin in cartridges.
d) Use of Humalog in an Insulin Infusion Pump:
Only certain Minimied and Diestronic insulin infusion pumps may be used to infuse insulin lispro. Before infusing insulin lispro, the manufacturer’s instructions should be studied to ascertain the sutiability or otherwise for the particular pump. Read and follow the instructions that accompany the infusion pump. Use the correct reservoir and catheter for the pump. Change the infusion set every 48 hours. Use aseptic techniques when inserting the infusion set. In the event of a hypoglycemic episode, the infusion should be stopped until the episode is resolved. If repeated or severe low blood glucose levels occurs, notify the your health care professional and consider the need to reduce or stop your insulin infusion. A pump malfunction or obstruction of the infusion set can result in a rapid rise in glucose levels. If an interruption to insulin flow is suspected, follow the instructions in the product literature and if appropriate, notify your health care professional. When used with an insulin infusion pump, Humalog should not be mixed with any other insulin.
e) Intravenous Administration of Insulin:
Intravenous injection of insulin lispro should be carried out following normal clinical practice for intravenous injections, for example, by an intravenous bolus or by an infusion system. Frequent monitoring of the blood glucose levels is required.
Infusion systems at concentrations from 0.1 U/ml to 1.0 U/ml insulin lispro in 0.9% sodium chloride or 5% dextrose are stable at room temperature for 48 hours. It is recommended that the system is primed before starting the infusion to the patient.
Insulins have no specific overdose definitions because serum glucose concentrations are a result of complex interactions between insulin levels, glucose availability and other metabolic processes. Hypoglycemia may occur as a result of an excess of insulin acitivity relative to food intake and energy expenditure.
Hypoglycemia may be associated with listlessness, confusion, palpitations, headache, sweating and vomiting.
Mild hypoglycemic episodes will respond to oral administration of glucose or other sugar or saccharated products.
Correction of moderately severe hypoglycaemia can be accomplished by intramuscular or subcutaneous administration of glucagon, followed by oral carbohydrate when the patient recovers sufficiently. Patients who fail to respond to glucagon must be given glucose solution intravenously.
If the patient is comatose, glucagon should be administered intramuscularly or subcutaneously. However, glucose solution must be given intravenously if glucagon is not available or if the patient fails to respond to glucagon. The patient should be given a meal as soon as consciousness is recovered.
Sustained carbohydrate intake and observation may be necessary because hypoglycaemia may recur after apparent clinical recovery.
Pregnancy and Lactation:
Data on a large number of exposed pregnancies do not indicate any adverse effect of insulin lispro on pregnancy or on the health of the fetus/newborn.
It is essential to maintain good control of the insulin-treated (insulin-dependent or gestational diabetes) patient through pregnancy. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. Patients with diabetes should be advised to inform their doctor if they are pregnant or are contemplating pregnancy. Careful monitoring of glucose control, as well as, general health, is essential in pregnant patients with diabetes.
Patients with diabetes who are lactating may require adjustments in insulin dose, diet or both.
Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (regular, NPH, lente, etc.), species (animal, human, human insulin analogue), and/or method of manufacture (recombinant DNA versus animal-source insulin) may result in the need for a change in dosage.
Conditions which may make the early warning symptoms of hypoglycemia different or less pronounced include long duration of diabetes, intensified insulin therapy, diabetic nerve disease or medications such as beta-blockers.
A few patients who have experienced hypogylcaemic reactions after transfer from animal-source insulin to human insulin have reported that the early warning symptoms of hypogylcaemia were less pronounced or different from those experienced with their previous insulin. Uncorrected hypogylcemic or hyperglycaemic reactions can cause loss of consciousness, coma or death.
The use of dosages which are inadequate or discontinuation of treatment, especially in insulin-dependent diabetics, may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal.
Insulin requirements may be reduced in the presence of renal impairment.
Insulin requirements may be reduced in patients with hepatic impairment due to reduced capacity for gluconeogenesis and reduced insulin breakdown; however, in patients with chronic hepatic impairment , an increase in insulin resistance may lead to increased insulin requirements.
Insulin requirements may be increased during illness or emotional disturbances.
Adjustment of dosage may also be necessary if patients undertake increased physical acitivity or change their usual diet. Exercise taken immediately after a meal may increase the risk of hypoglycaemia. A consequence of the pharmacodynamics of rapid-acting insulin analogues is that if hypoglycaemia occurs, it may occur earlier after an injection when compared with soluble human insulin.
If the 40 U/ml vial is the product normally prescribed, do no take insulin from a 100 U/ml cartridge using a 40 U/ml syringe.
Humalog should only be used in children in preference to soluble insulin when a fast action of insulin might be beneficial. For example, in the timing of the injections in relations to meals.
Effect on the ability to drive and use machines:
The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).
Patients should be advised to take precautions to avoid hypoglycaemia whilst driving, this is paritculary important in those who have reduced or absent awareness of the warning signs of hypogylcemia or have frequent episodes of hypogylcaemia. The advisability of driving should be considered in these circumstances.
Pack of 5 cartridges of 3 ml each, or 5 kwik-pens of 3 ml each.
After inserting the cartridge in a pen, the solution should be used in 28 days, when stored below 30°C.
Store at 2-8°C (refrigerated). Do not freeze. Do not expose to excessive heat or direct sunlight. Once in use, cartridges may be used for up to 28 days.