Humulin nph

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HUMULIN NPH (HUMULIN® NPH)

Composition:

Active substance: human isophane insulin (recombinant DNA origin);

1 ml of suspension contains 100 IU of human isophane insulin (recombinant DNA origin);

Excipients: metacresol; glycerol; phenol; protamine sulfate; sodium hydrogen phosphate heptahydrate; zinc oxide; hydrochloric acid, 10% solution; sodium hydroxide, 10% solution; water for injections.

Pharmaceutical form. Injection suspension.

Main physicochemical properties: white suspension, which upon standing forms a white sediment and a colorless or almost colorless supernatant liquid. The sediment is easily resuspended by gentle shaking.

Pharmacotherapeutic group. Antidiabetic agents. Intermediate-acting insulins and analogues. ATC code A10AC01.

Pharmacological properties.

Pharmacodynamics.

Humulin NPH is an intermediate-acting insulin preparation.

The primary action of insulin is the regulation of glucose metabolism. In addition, insulin affects various anabolic and anticatabolic processes in different tissues. In muscle tissue, these effects include enhanced synthesis of glycogen, fatty acids, glycerol, and protein, as well as increased amino acid uptake, accompanied by suppression of glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, protein catabolism, and amino acid release.

The figure below shows the typical insulin activity profile (glucose utilization curve) as a bold line following subcutaneous injection. The possible variability in duration and/or intensity of insulin activity among different patients is illustrated by the shaded area on the graph. Individual variability depends on factors such as dose volume, temperature at the injection site, and the patient's level of physical activity.

Time (hours)

Pharmacokinetics.

Humulin NPH is human insulin produced using recombinant DNA technology.

The pharmacokinetics of insulin does not reflect the metabolic activity of the hormone. Therefore, when considering insulin activity, studying glucose utilization curves (shown above) is more appropriate.

No serious adverse effects associated with the use of the drug were observed during toxicological studies.

Clinical characteristics.

Indications.

Treatment of patients with diabetes mellitus who require insulin administration to maintain normal glucose homeostasis.

Contraindications.

Hypoglycemia. Hypersensitivity to the active substance or to any of the excipients of the product, except in cases of administration as desensitizing therapy. Intravenous administration is contraindicated.

Interaction with other medicinal products and other forms of interaction.

Some medicinal products affect glucose metabolism; therefore, consultation with a physician is recommended regarding the concomitant use of any other medicinal products with human insulin. The physician should consider possible interactions if the patient is taking any other medicinal products.

Insulin requirement may increase when using medicinal products with hyperglycemic activity, such as glucocorticoids, thyroid hormones, growth hormone, danazol, β2-sympathomimetics (e.g., ritodrine, salbutamol, terbutaline), thiazides.

Insulin requirement may decrease when using medicinal products with hypoglycemic activity, such as oral hypoglycemic agents, salicylates (e.g., acetylsalicylic acid), certain antidepressants (monoamine oxidase inhibitors), certain angiotensin-converting enzyme inhibitors (captopril, enalapril), angiotensin II receptor blockers, non-selective beta-blockers, or alcohol.

Somatostatin analogs (octreotide, lanreotide) may either increase or decrease insulin requirement.

Special precautions for use.

Any change in the type or brand of insulin must be carried out under close medical supervision. Changes in concentration, brand (manufacturer), type (soluble, NPH, mixed), species (animal insulin, human insulin, human insulin analog), and/or method of production (recombinant DNA insulin or animal insulin) may require dosage adjustment.

Dosage requirements when using human insulin may differ from those when using animal insulin. Dose adjustments may be required starting with the first dose or during the first several weeks or months of treatment.

In some patients who developed hypoglycemic reactions after switching from animal insulin to human insulin, early warning symptoms of hypoglycemia were less pronounced or different compared to those previously experienced during treatment with animal insulin. Patients with significant improvement in blood glucose levels (e.g., due to intensified insulin therapy) may no longer experience some or any of the early warning symptoms of hypoglycemia, and they should be informed about this. Conditions in which early warning symptoms of hypoglycemia may be less specific or less pronounced include long-standing diabetes, diabetic neuropathy, or concomitant use of medications such as beta-adrenergic blockers.

Untreated hypoglycemic or hyperglycemic reactions may lead to loss of consciousness, coma, and potentially fatal outcomes.

Use of inappropriate doses or abrupt discontinuation of treatment, especially in insulin-dependent diabetes, may lead to hyperglycemia and ketoacidosis—conditions that are potentially life-threatening.

Antibody formation may occur during treatment with human insulin, although to a lesser extent than with purified animal insulin.

Insulin requirements may change significantly in diseases of the adrenal glands, pituitary, thyroid gland, and in the presence of renal or hepatic insufficiency.

Insulin requirements may also increase during illness or emotional stress.

Dose adjustments may be necessary when there is a change in the intensity of physical activity or in usual dietary patterns.

Patients should be instructed to rotate injection sites regularly to reduce the risk of developing lipodystrophy or cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and impaired glycemic control following insulin injections into areas affected by these reactions. Cases of hypoglycemia have been reported after sudden changes in injection sites to areas not affected by amyloidosis or lipodystrophy. After changing injection sites, blood glucose monitoring is recommended, and dose adjustments of antidiabetic agents may need to be considered.

Combination with pioglitazone

Cases of heart failure have been reported with concomitant use of pioglitazone and insulin, particularly in patients with risk factors for heart failure. This information should be taken into account when prescribing the combination of Humulin NPH and pioglitazone. When using this combination, patients should be monitored for symptoms of heart failure, weight gain, and edema. Pioglitazone treatment should be discontinued if cardiac symptoms worsen.

Traceability

To improve traceability of biological medicinal products, the name and batch number of the administered product should be clearly documented.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose unit, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Patients with insulin-dependent diabetes mellitus or gestational diabetes receiving insulin therapy require careful monitoring throughout pregnancy. Insulin requirements typically decrease during the first trimester of pregnancy and then increase during the second and third trimesters. Patients with diabetes should inform their physician if they become pregnant or are planning pregnancy.

During pregnancy, patients with diabetes require careful monitoring of blood glucose levels and overall health status.

Breastfeeding women with diabetes may require adjustments in insulin dosage and/or dietary regimen.

Ability to affect reaction speed when driving or operating machinery

The ability of patients using insulin to concentrate and react may be impaired as a result of hypoglycemia. This may constitute a risk factor when such abilities are particularly important (including while driving a vehicle or operating machinery).

Patients should be informed about the specific preventive measures necessary to avoid hypoglycemia while driving. This is especially important for patients who have reduced or absent awareness of hypoglycemic warning symptoms or who frequently experience episodes of hypoglycemia. In such circumstances, the appropriateness of driving should be evaluated.

Method of Administration and Dosage

The dose is determined by the physician according to the patient's individual needs.

Humulin NPH should be administered only by subcutaneous injection, using a reusable pen-injector (for the cartridge formulation) or a pre-filled pen-injector (for the pen formulation, such as the KwikPen). Humulin NPH must not be administered intravenously.

Subcutaneous injections should be given in the abdominal wall, thigh, buttocks, or upper arm. Injection sites should be rotated to avoid using the same site more than once a month, in order to reduce the risk of developing lipodystrophy and cutaneous amyloidosis (see sections "Special Warnings" and "Adverse Reactions").

Care should be taken during administration of Humulin NPH to avoid accidental intravascular injection. The injection site should not be massaged after injection. Patients must be trained in the correct injection technique.

Instructions for Use of the Medicinal Product

Each pen-injector/cartridge must be used by only one patient, even if the needle is changed, to prevent the possible transmission of infectious agents.

Humulin NPH in cartridges must be used only with reusable pen-injectors manufactured by Eli Lilly and Company and its affiliates. It should not be used with other reusable pen-injectors, as the accuracy of dosing has not been established for such devices.

a) Preparing the Dose

Immediately before administration, the insulin in Humulin NPH cartridges must be resuspended by rolling the cartridge gently between the palms 10 times and inverting it 180° 10 times until the suspension appears uniformly cloudy or uniformly milky. If the liquid does not achieve the proper appearance, repeat the mixing procedure until the contents are fully resuspended. The cartridges contain a small glass bead to aid in resuspension. Do not shake the cartridge vigorously, as this may cause foaming, which could interfere with accurate dose measurement.

The appearance of the cartridge contents should be checked regularly. Do not use the cartridge if the suspension contains clumps or if white particles adhere to the bottom or sides of the cartridge, making the glass appear cloudy.

Cartridges are not intended for mixing different insulins. Empty cartridges must not be reused.

For instructions on loading the cartridge into the pen-injector, attaching the needle, and administering the insulin injection, refer to the manufacturer's instructions for the pen-injector.

b) Administration of the Medicinal Product

The prescribed insulin dose should be administered according to the physician's instructions.

Instructions for Use

Each time a new KwikPen pre-filled with Humulin NPH is used, the patient should carefully read the Instructions for Use, as they may contain updated information. This information does not replace the necessity of discussing the patient's health status and prescribed treatment with a physician.

The pre-filled KwikPen containing Humulin NPH is a single-use pen-injector containing 300 IU (3 mL) of insulin. Multiple injections can be administered using one pen. The dose increment is 1 unit. Doses from 1 to 60 units of insulin can be set for a single injection. If a dose greater than 60 units is required, two or more injections should be administered. After each injection, the plunger moves slightly, and its movement may not be easily noticeable. The plunger will reach the end of the cartridge only after all 300 units have been used.

It is not recommended that patients with complete vision loss or impaired vision use the pen-injector without assistance from individuals trained in its proper use.

Schematic Diagram of the KwikPen Pen-injector

Description of the Humulin NPH QuickPen

The pen body is beige in color, and the button is green.

The label is white with a light green stripe.

The use of the QuickPen is recommended only with Becton, Dickinson and Company (BD) needles.

Preparing the QuickPen

• Wash hands with soap.
• Read the label on the pen to ensure that the patient is using the correct type of insulin. This is especially important if the patient uses more than one type of insulin.
• Do not use the pen after the expiration date indicated on the label. Do not use the pen for more than 28 days, even if there is still insulin remaining in it.
• Always use a new needle for each injection to prevent infection and needle blockage.

Checking the KwikPen insulin pen for insulin flow

The insulin flow check for the KwikPen insulin pen should be performed before each injection.

• Checking the KwikPen insulin pen for insulin flow is necessary to remove any air that may have accumulated in the needle or insulin cartridge during normal use, and to ensure that the pen is working properly.
• If the patient does not perform the insulin flow check before each injection, they may receive either too low or too high a dose of insulin.

Dose Setting

• Doses from 1 to 60 units of insulin can be set for a single injection.
• If a dose exceeding 60 units is required, two or more injections should be administered.
  • If assistance is needed in deciding how exactly to divide the dose, consult your doctor.
  • For each separate injection, use a new needle and repeat the insulin flow check.

• The pen will not allow a dose to be dialed that exceeds the number of units remaining in the pen.
  • If a dose greater than the number of units remaining in the pen is required, you may inject the remaining units and then complete the dose using a new pen, or administer the full dose using a new pen.
• It is normal for a small amount of insulin to remain in the pen that cannot be injected.

Administering a dose

• Use the injection technique recommended by your doctor.
• Always rotate injection sites.
• Never attempt to change the dose during insulin injection.

After injection.

Children.

The dosage, administration schedule, and number of injections for children should be determined by the physician according to individual patient needs and specific clinical circumstances.

Overdose.

There is no specific definition for insulin overdose, as blood glucose levels result from a complex interaction between insulin levels, glucose intake, and other metabolic processes. Hypoglycemia may occur due to an excess of insulin relative to the amount of food intake and energy expenditure.

Symptoms of hypoglycemia include lethargy, confusion, tachycardia, headache, sweating, and vomiting.

Mild hypoglycemia is usually corrected by oral administration of glucose or sugar-containing products. Moderate to severe hypoglycemia may be managed by intramuscular or subcutaneous administration of glucagon, followed by oral carbohydrates once the patient's condition has stabilized. For patients who do not respond to glucagon, intravenous glucose administration is required. If the patient is unconscious, glucagon should be administered intramuscularly or subcutaneously. In the absence of glucagon or if there is no response to glucagon, intravenous glucose solution must be administered. The patient should be fed as soon as he or she regains consciousness.

Continued carbohydrate intake and medical monitoring may be necessary, as hypoglycemia may recur after apparent clinical improvement.

Adverse reactions.

Hypoglycaemia is the most common adverse effect of insulin therapy in patients with diabetes mellitus. Severe hypoglycaemia may lead to loss of consciousness and, in some cases, to fatal outcomes. The exact frequency of hypoglycaemic episodes cannot be determined, as it results from the combined influence of insulin dose and other factors such as the patient's diet composition and level of physical activity.

Local allergic reactions may occur frequently (frequency from 1/100 to <1/10), including injection site reactions such as skin redness, swelling, and itching. These reactions usually resolve within a period of several days to several weeks. Sometimes, such conditions are not related to insulin itself but to other factors, for example, the presence of irritant substances in skin cleansing agents or inadequate injection technique.

Systemic allergic reaction is very rare (<1/10,000), but potentially represents a more serious adverse effect and constitutes a generalized allergic reaction to insulin. It may manifest as generalized rash, dyspnoea, wheezing, hypotension, tachycardia, and increased sweating. Severe cases of generalized allergy can be life-threatening. In exceptional cases of severe allergic reaction to Humulin NPH, appropriate measures should be taken immediately. Insulin substitution or desensitization therapy may be required.

Lipodystrophy at the injection site occurs infrequently (frequency from 1/1000 to <1/100).

Skin and subcutaneous tissue disorders: cutaneous amyloidosis, occurring at an unknown frequency.

Lipodystrophy and cutaneous amyloidosis may develop at the injection site, which can delay local absorption of insulin. Regular rotation of injection sites within a given injection area may help reduce or prevent these reactions (see section "Special instructions").

Cases of oedema have been reported during insulin therapy, particularly when previous poor metabolic control is improved by intensive insulin treatment.

Shelf life. 3 years.

Storage conditions. Store out of reach of children and in a cool place at a temperature of 2 °C to 8 °C. Avoid freezing.

During use, store at room temperature of 15–25 °C for up to 28 days, protected from excessive heat or direct sunlight.

Incompatibility.

Humulin NPH must not be mixed with insulins from other manufacturers or with animal-sourced insulins.

Packaging. 3 ml glass cartridges; 5 cartridges in a cardboard pack. 3 ml glass cartridges in QuickPen injection pens; 5 pens in a cardboard pack.

Prescription status. Prescription only.

Manufacturer. Lilly France, France.

Manufacturer's address and place of business.

Zone Industrielle 2, Rue du Colonel Lilly, 67640 Fegersheim, France.