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Insulin NPH

Pronunciation

(IN soo lin N P H)

Index Terms

  • Isophane Insulin
  • NPH Insulin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Suspension, Subcutaneous:

HumuLIN N: 100 units/mL (3 mL, 10 mL) [contains metacresol, phenol]

NovoLIN N: 100 units/mL (10 mL) [contains metacresol, phenol]

NovoLIN N ReliOn: 100 units/mL (10 mL) [contains metacresol, phenol]

Suspension Pen-injector, Subcutaneous:

HumuLIN N KwikPen: 100 units/mL (3 mL) [contains metacresol, phenol]

HumuLIN N Pen: 100 units/mL (3 mL [DSC]) [contains metacresol, phenol]

Brand Names: U.S.

  • HumuLIN N KwikPen [OTC]
  • HumuLIN N Pen [OTC] [DSC]
  • HumuLIN N [OTC]
  • NovoLIN N ReliOn [OTC]
  • NovoLIN N [OTC]

Pharmacologic Category

  • Insulin, Intermediate-Acting

Pharmacology

Insulin acts via specific membrane-bound receptors on target tissues to regulate metabolism of carbohydrate, protein, and fats. Target organs for insulin include the liver, skeletal muscle, and adipose tissue.

Within the liver, insulin stimulates hepatic glycogen synthesis. Insulin promotes hepatic synthesis of fatty acids, which are released into the circulation as lipoproteins. Skeletal muscle effects of insulin include increased protein synthesis and increased glycogen synthesis. Within adipose tissue, insulin stimulates the processing of circulating lipoproteins to provide free fatty acids, facilitating triglyceride synthesis and storage by adipocytes; also directly inhibits the hydrolysis of triglycerides. In addition, insulin stimulates the cellular uptake of amino acids and increases cellular permeability to several ions, including potassium, magnesium, and phosphate. By activating sodium-potassium ATPases, insulin promotes the intracellular movement of potassium.

Normally secreted by the pancreas, insulin products are manufactured for pharmacologic use through recombinant DNA technology using either E. coli or Saccharomyces cerevisiae. Insulins are categorized based on the onset, peak, and duration of effect (eg, rapid-, short-, intermediate-, and long-acting insulin). Insulin NPH, an isophane suspension of human insulin, is an intermediate-acting insulin.

Excretion

Urine

Onset of Action

1-2 hours; Peak effect: 4-12 hours

Time to Peak

Plasma: 6-10 hours

Duration of Action

14-24 hours

Use: Labeled Indications

Treatment of type 1 diabetes mellitus (insulin dependent, IDDM) and type 2 diabetes mellitus (noninsulin dependent, NIDDM) to improve glycemic control

Use: Unlabeled

Gestational diabetes mellitus (GDM)

Contraindications

Hypersensitivity to insulin NPH or any component of the formulation

Dosing: Adult

Diabetes mellitus: Note: Insulin NPH is an intermediate-acting insulin formulation which is usually administered subcutaneously once or twice daily. When compared to insulin regular, insulin NPH has a slower onset and longer duration of activity. Insulin requirements vary dramatically between patients and dictate frequent monitoring and close medical supervision.

Diabetes mellitus, type 1: SubQ:

General insulin dosing:

Note: Multiple daily doses are utilized and guided by blood glucose monitoring. Combinations of different insulin formulations are commonly used. The daily doses presented below are expressed as the total units/kg/day of all insulin formulations combined. Insulin NPH is not intended for initial therapy; basal insulin requirements should be established first to direct dosing of combination insulin products.

Usual maintenance range: SubQ: 0.5 to 1 units/kg/day in divided doses. An estimate of anticipated needs may be based on body weight and/or activity factors as follows:

Nonobese: 0.4 to 0.6 units/kg/day

Obese: 0.8 to 1.2 units/kg/day

Pubescent Children and Adolescents: During puberty, requirements may substantially increase to >1 unit/kg/day and in some cases up to 2 units/kg/day (IDF-ISPAD, 2011).

Division of daily insulin requirement ("conventional therapy"): Generally, 50% to 75% of the total daily dose (TDD) is given as an intermediate-acting (eg, NPH) or a long-acting form of insulin (in 1 to 2 daily injections). The remaining portion of the TDD is then divided and administered before or at mealtimes (depending on the formulation) as a rapid-acting or short-acting form of insulin.

Adjustment of dose: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Adjust dose to maintain premeal and bedtime glucose in target range. Since combinations of agents are frequently used, dosage adjustment must address the individual component of the insulin regimen which most directly influences the blood glucose value in question, based on the known onset and duration of the insulin component. Treatment and monitoring regimens must be individualized. Also see Additional Information or Pharmacotherapy Pearls.

Diabetes mellitus, type 2: Augmentation therapy (patients for which diet, exercise, weight reduction, and oral hypoglycemic agents have not been adequate): SubQ: Initial dosage of 0.2 units/kg/day or 10 units/day of an intermediate-acting (eg, NPH) or long-acting insulin administered at bedtime has been recommended. As an alternative, regular insulin or rapid-acting insulin formulations administered before meals have also been used. Dosage must be carefully adjusted.

General considerations for insulin use in type 2 diabetes:

Timing of initiation: The goal of therapy is to achieve an HbA1c <7%. According to a position statement by the ADA and European Association for the Study of Diabetes (EASD), dual therapy (metformin + a second antihyperglycemic agent) is recommended in patients with type 2 diabetes who fail to achieve glycemic goals after ~3 months with lifestyle interventions and metformin monotherapy (unless contraindications to metformin exist). Preference is not given for adding insulin or a noninsulin agent as the second antihyperglycemic agent (drug choice should be individualized based on patient characteristics). However, insulin should be considered as part of a combination regimen when hyperglycemia is severe, particularly if patient is symptomatic or has catabolic features (eg, weight loss, ketosis). If insulin is selected, the addition of basal insulin (ie, a long-acting insulin such as glargine or detemir) is recommended. If HbA1c target not achieved after ~3 months of dual therapy, may proceed to triple therapy (Inzucchi 2015).

Intensification of therapy: If HbA1c target has not been met, despite titrating basal insulin (ie, long-acting insulin) to provide acceptable fasting blood glucose concentrations, intensification of therapy should be considered to cover postprandial glucose excursions. Options include adding a mealtime insulin (1 to 3 injections of a rapid-acting insulin analog [lispro, aspart, glulisine]) or adding a GLP-1 receptor agonist (eg, exenatide, liraglutide). Alternatively, although less studied, may transition from basal insulin (ie, long-acting insulin) to a twice daily premixed (or biphasic) insulin analog (70/30 aspart mix, 75/25 or 50/50 lispro mix) (Inzucchi 2015).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Diabetes mellitus, type 1: SubQ: Children and Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment provided in manufacturer’s labeling; insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely.

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer’s labeling; insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely.

Dosing: Obesity

Refer to indication-specific dosing for obesity-related information (may not be available for all indications).

Reconstitution

For SubQ administration:

Humulin® N vials: May be diluted with the universal diluent, Sterile Diluent for Humalog®, Humulin® N, Humulin® R, Humulin® 70/30, and Humulin® R U-500. Do not dilute insulin contained in a cartridge or prefilled pen.

Novolin® N: Insulin Diluting Medium for NovoLog® is not intended for use with Novolin® N or any insulin product other than insulin aspart.

Administration

SubQ administration: For subcutaneous administration into the thigh, upper arm, buttocks, or abdomen; do not administer IM or IV, or in an insulin pump. Rotate injection sites within the same region to reduce the risk of lipodystrophy. In order to properly resuspend the insulin, vials should be carefully shaken or rolled several times, prefilled pens should be rolled between the palms ten times and inverted 180° ten times, and cartridges should be inverted 180° at least ten times. Properly resuspended insulin NPH should look uniformly cloudy or milky; do not use if any white insulin substance remains at the bottom of the container, if any clumps are present, or if white particles are stuck to the bottom or wall of the container. Cold injections should be avoided. When mixing insulin NPH with other preparations of insulin (eg, insulin aspart, insulin glulisine, insulin lispro, insulin regular), insulin NPH should be drawn into the syringe after the other insulin preparations. Do not dilute or mix other insulin formulations with insulin NPH contained in a cartridge or prefilled pen.

Dietary Considerations

Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.

Compatibility

Note: A universal sterile diluent, Sterile Diluent for Humalog®, Humulin® N, Humulin® R, Humulin® 70/30, and Humulin® R U-500, is available from the manufacturer for SubQ administration.

Compatibility in syringe: Incompatible with insulin detemir, insulin glargine.

Storage

Humulin® N vials: Store unopened vials in refrigerator between 2°C and 8°C (36°F to 46°F; do not freeze; keep away from heat and sunlight. Once punctured (in use), vials may be stored for up to 31 days in the refrigerator between 2°C and 8°C (36°F to 46°F) or at room temperature ≤30°C (≤86°F)

Humulin® N pens and cartridges: Store unopened pens and unused cartridges in the refrigerator between 2°C and 8°C (36°F to 46°F); do not freeze; keep away from heat and sunlight. Once punctured (in use), cartridge/pen should be stored at room temperature 15°C to 30°C (59°F to 86°F) for up to 14 days.

Novolin® N vials: Store unopened vials in refrigerator between 2°C and 8°C (36°F to 46°F) until product expiration date or at room temperature ≤25°C (≤77°F) for up to 42 days; do not freeze; keep away from heat and sunlight. Once punctured (in use), store vials at room temperature ≤25°C (≤77°F) for up to 42 days (this includes any days stored at room temperature prior to opening vial); refrigeration of in-use vials is not recommended.

Canadian labeling (not in U.S. labeling): All products: Unopened vials, cartridges, and pens should be stored under refrigeration between 2°C and 8°C (36°F to 46°F) until the expiration date; do not freeze; keep away from heat and sunlight. Once punctured (in use), Humulin® vials, cartridges and pens should be stored at room temperature <25°C (<77°F) for up to 4 weeks. Once punctured (in use), Novolin® ge vials, cartridges, and pens may be stored for up to 1 month at room temperature <25°C (<77°F) for vials or <30°C (<86°F) for pens/cartridges; do not refrigerate.

For SubQ administration: Humulin® N vials: According to the manufacturer, storage and stability information are not available for diluted Humulin® N.

Drug Interactions

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Beta-Blockers: May enhance the hypoglycemic effect of Insulin. Exceptions: Levobunolol; Metipranolol. Monitor therapy

DPP-IV Inhibitors: May enhance the hypoglycemic effect of Insulin. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Edetate CALCIUM Disodium: May enhance the hypoglycemic effect of Insulin. Monitor therapy

Edetate Disodium: May enhance the hypoglycemic effect of Insulin. Monitor therapy

GLP-1 Agonists: May enhance the hypoglycemic effect of Insulin. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Exceptions: Liraglutide. Consider therapy modification

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Liraglutide: May enhance the hypoglycemic effect of Insulin. Management: If liraglutide is used for the treatment of diabetes (Victoza), consider insulin dose reductions. The combination of liraglutide and insulin should be avoided if liraglutide is used exclusively for weight loss (Saxenda). Consider therapy modification

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Metreleptin: May enhance the hypoglycemic effect of Insulin. Management: Insulin dosage adjustments (including potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of metreleptin. Monitor closely. Consider therapy modification

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pioglitazone: May enhance the adverse/toxic effect of Insulin. Specifically, the risk for hypoglycemia, fluid retention, and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone, dose reductions should be considered to reduce the risk of hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure. Consider therapy modification

Pramlintide: May enhance the hypoglycemic effect of Insulin. Management: Upon initiation of pramlintide, decrease mealtime insulin dose by 50% to reduce the risk of hypoglycemia. Monitor blood glucose frequently and individualize further insulin dose adjustments based on glycemic control. Consider therapy modification

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Rosiglitazone: Insulin may enhance the adverse/toxic effect of Rosiglitazone. Specifically, the risk of fluid retention, heart failure, and hypoglycemia may be increased with this combination. Avoid combination

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

SGLT2 Inhibitors: May enhance the hypoglycemic effect of Insulin. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Adverse Reactions

Frequency not defined.

Cardiovascular: Peripheral edema

Endocrine & metabolic: Hypoglycemia, hypokalemia, weight gain

Hypersensitivity: Hypersensitivity reaction

Immunologic: Immunogenicity

Local: Atrophy at injection site, hypertrophy at injection site, injection site reaction (including redness, swelling, and itching)

Neuromuscular & skeletal: Swelling of extremities

Ophthalmic: Visual disturbance

Warnings/Precautions

Concerns related to adverse effects:

• Hypoglycemia: The most common adverse effect of insulin is hypoglycemia. The timing of hypoglycemia differs among various insulin formulations. Hypoglycemia may result from increased work or exercise without eating; use of long-acting insulin preparations (eg, insulin detemir, insulin glargine) may delay recovery from hypoglycemia. Profound and prolonged episodes of hypoglycemia may result in convulsions, unconsciousness, temporary or permanent brain damage or even death. Insulin requirements may be altered during illness, emotional disturbances or other stressors. Instruct patients to use caution with ethanol; may increase risk of hypoglycemia.

• Hypokalemia: Insulin (especially IV insulin) causes a shift of potassium from the extracellular space to the intracellular space, possibly producing hypokalemia. If left untreated, hypokalemia may result in respiratory paralysis, ventricular arrhythmia and even death. Use with caution in patients at risk for hypokalemia (eg, loop diuretic use). Monitor serum potassium and supplement potassium when necessary.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment. Dosage requirements may be reduced.

• Renal impairment: Use with caution in patients with renal impairment. Dosage requirements may be reduced.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Multiple dose injection pens: According to the Centers for Disease Control and Prevention (CDC), pen-shaped injection devices should never be used for more than one person (even when the needle is changed) because of the risk of infection. The injection device should be clearly labeled with individual patient information to ensure that the correct pen is used (CDC, 2012).

Other warnings/precautions:

• Administration: Insulin NPH is NOT intended for IV or IM administration.

• Appropriate use: Diabetes mellitus: The general objective of exogenous insulin therapy is to approximate the physiologic pattern of insulin secretion which is characterized by two distinct phases. Phase 1 insulin secretion suppresses hepatic glucose production and phase 2 insulin secretion occurs in response to carbohydrate ingestion; therefore, exogenous insulin therapy may consist of basal insulin (eg, intermediate- [insulin NPH] or long-acting insulin or via continuous subcutaneous insulin infusion [CSII]) and/or preprandial insulin (eg, short- or rapid-acting insulin) (see Related Information: Insulin Products). Patients with type 1 diabetes do not produce endogenous insulin; therefore, these patients require both basal and preprandial insulin administration. Patients with type 2 diabetes retain some beta-cell function in the early stages of their disease; however, as the disease progresses, phase 1 insulin secretion may become completely impaired and phase 2 insulin secretion becomes delayed and/or inadequate in response to meals. Therefore, patients with type 2 diabetes may be treated with oral antidiabetic agents, basal insulin, and/or preprandial insulin depending on the stage of disease and current glycemic control. Since treatment regimens often consist of multiple agents, dosage adjustments must address the specific phase of insulin release that is primarily contributing to the patient’s impaired glycemic control. Treatment and monitoring regimens must be individualized.

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

Monitoring Parameters

Diabetes mellitus: Plasma glucose, electrolytes, HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2016a])

Pregnancy Risk Factor

B

Pregnancy Considerations

Animal reproduction studies have not been conducted; however, use provides maternal and fetal benefits.

In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2016d; Kitzmiller 2008; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ACOG 2013; ADA 2016d; Blumer 2013; Kitzmiller 2008; Lambert 2013). Prior to pregnancy, effective contraception should be used until glycemic control is achieved (ADA 2016d; Kitzmiller 2008).

Insulin requirements tend to fall during the first trimester of pregnancy and increase in the later trimesters, peaking at 28 to 32 weeks of gestation. Following delivery, insulin requirements decrease rapidly (ACOG 2005). NPH insulin may be used to treat diabetes in pregnant women (Blumer 2013; Kitzmiller 2008; Lambert 2013).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), vision changes, chills, burning or numbness feeling, arrhythmia, severe dizziness, passing out, mood changes, seizures, slurred speech, severe injection site irritation, or change in skin to thick or thin at injection site (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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