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Insulin NPH

Medically reviewed on March 25, 2018

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.

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]

Brand Names: U.S.

  • HumuLIN N KwikPen [OTC]
  • 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 to 2 hours; Peak effect: 4 to 12 hours

Time to Peak

Plasma: 6 to 10 hours

Duration of Action

14 to 24 hours

Use: Labeled Indications

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

Off Label Uses

Gestational diabetes mellitus

Based on the American College of Obstetricians and Gynecologists Practice Bulletin for the management of gestational diabetes mellitus (GDM) and the American Diabetes Association Standards of Medical Care for the management of diabetes in pregnancy, insulin may be used to treat GDM when nutrition and exercise therapy are not effective.

Contraindications

Hypersensitivity to insulin NPH or any component of the formulation; during periods of hypoglycemia

Dosing: Adult

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 (off-label):

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.

Initial total insulin dose: SubQ: 0.2 to 0.6 units/kg/day in divided doses. Conservative initial doses of 0.2 to 0.4 units/kg/day are often recommended to avoid the potential for hypoglycemia. A rapid-acting insulin may be the only insulin formulation used initially.

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

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 (eg, lispro, aspart, glulisine) or short-acting (regular) form of insulin.

Division of daily insulin requirement (“intensive therapy”): Basal insulin delivery with 1 or 2 doses of intermediate- or long-acting insulin formulations superimposed with doses of short-acting (regular) insulin or rapid-acting insulin (eg, lispro, aspart, glulisine) formulations 3 or more times daily.

Dosage adjustment: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. 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.

Diabetes mellitus, type 2: SubQ:

Off-label:

Initial: 0.1 to 0.2 units/kg/day or 10 units/day. Note: Longer acting basal insulin analogs are generally preferred to reduce hypoglycemia risk; however NPH insulin may be considered in patients without a history of hypoglycemia (ADA 2017f)

Dosage adjustment:

To reach self-monitoring glucose target: Adjust dose by 10% to 15% or 2 to 4 units; may adjust at weekly or twice weekly intervals (ADA 2017f)

For hypoglycemia: If no clear reason for hypoglycemia, decrease dose by 4 units or by 10% to 20% (ADA 2017f)

Surgical patients: On the morning of surgery or procedure, give 60% to 80% of the usual dose of long-acting analogs (eg, detemir, glargine, or degludec) or pump “basal” insulin (rapid-or short-acting insulins) (ADA 2017d)

General considerations for insulin use in type 2 diabetes:

Timing of initiation: Dual therapy (metformin + a second antihyperglycemic agent) and then triple therapy (metformin + two antihyperglycemic agents) is recommended in patients who fail to achieve glycemic goals after ~3 months with lifestyle intervention and metformin monotherapy or dual therapy, respectively (unless contraindications to metformin exist). Preference is not given for which agent(s) should be added to metformin (drug choice should be individualized based on patient characteristics). If HbA1c target not achieved after ~3 months of triple therapy, consider initiating basal insulin (usually with metformin +/- other noninsulin agent) or if patient already receiving an optimally titrated basal insulin (ie, a long-acting insulin such as glargine, degludec, or detemir) as part of their regimen, consider combination injectable therapy (ADA 2017f).

Combination injectable therapy: If HbA1c target has not been met with basal insulin (ie, long-acting insulin such as glargine, degludec or detemir) (usually combined with metformin +/- other noninsulin agent), despite titrating basal insulin to provide acceptable fasting blood glucose concentrations, combination injectable therapy should be considered. Options include: adding a rapid-acting insulin (eg, lispro, aspart, glulisine) prior to largest meal or adding a GLP-1 receptor agonist or changing from basal insulin to a twice daily premixed insulin. If HbA1c still not adequately controlled, consider advancing from one rapid-acting insulin prior to largest meal to ‘basal-bolus’ regimen (ie, rapid-acting insulin administered before ≥2 meals) or consider advancing from a twice daily premixed insulin to a three times daily premixed insulin (ADA 2017f).

Patients with elevated HbA1C at therapy initiation: If HbA1c is ≥9% at initiation of therapy, dual therapy (metformin + a second antihyperglycemic agent) should be considered. If HbA1c ≥10%, blood glucose is ≥300 mg/dL or if patient is symptomatic (eg, polyuria, polydipsia), insulin therapy (with or without additional agents) should be considered (ADA 2017f).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

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: Children and Adolescents: Note: Multiple daily doses are utilized and guided by blood glucose monitoring. Combinations of 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.

Usual maintenance range: SubQ: 0.5 to 1 unit/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)

Dosage adjustment: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Since combinations of agents are frequently used, dosage adjustment must address the individual component of the insulin regimen that most directly influences the blood glucose value in question, based on the known onset and duration of the insulin component.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the 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).

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 [Canadian product] 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. Per the manufacturer labeling, Humulin N from a vial may be mixed with insulin lispro or insulin regular and Novolin N from a vial may be mixed only with insulin regular. When mixing insulin NPH with other insulins in a syringe, 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 [Canadian product] or prefilled pen.

Dietary Considerations

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

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 KwikPen: Store unopened 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), should be stored below 30°C (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 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.

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 Insulins. Exceptions: Levobunolol; Metipranolol. Monitor therapy

Dipeptidyl Peptidase-IV Inhibitors: May enhance the hypoglycemic effect of Insulins. 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 Insulins. Monitor therapy

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

Glucagon-Like Peptide-1 Agonists: May enhance the hypoglycemic effect of Insulins. 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

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

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 Insulins. 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

Macimorelin: Insulins may diminish the diagnostic effect of Macimorelin. Avoid combination

Metreleptin: May enhance the hypoglycemic effect of Insulins. 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

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

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

Pioglitazone: May enhance the adverse/toxic effect of Insulins. 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 Insulins. 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

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

Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones 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

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Rosiglitazone: Insulins 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

Sodium-Glucose Cotransporter 2 (SLGT2) Inhibitors: May enhance the hypoglycemic effect of Insulins. 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:

• Hypersensitivity: Hypersensitivity reactions (serious, life-threatening and anaphylaxis) have occurred. If hypersensitivity reactions occur, discontinue administration and initiate supportive care measures.

• 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.

Special populations:

• Hospitalized patients with diabetes: Exclusive use of a sliding scale insulin regimen (insulin regular) in the inpatient hospital setting is strongly discouraged. In the critical care setting, continuous IV insulin infusion (insulin regular) has been shown to best achieve glycemic targets. In noncritically ill patients with either poor oral intake or taking nothing by mouth, basal insulin or basal plus bolus is preferred. In noncritically ill patients with adequate nutritional intake, a combination of basal insulin, nutritional, and correction components is preferred. An effective insulin regimen will achieve the goal glucose range without the risk of severe hypoglycemia). A blood glucose value <70 mg/dL should prompt a treatment regimen review and change, if necessary, to prevent further hypoglycemia (ADA 2017d).

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]); renal function, hepatic function, weight

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 2017c; 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 2017c; Blumer 2013; Kitzmiller 2008; Lambert 2013).

Insulin therapy is the preferred treatment of type 1 and type 2 diabetes in pregnant women, as well as GDM when pharmacologic therapy is needed (ADA 2017c). Insulin requirements tend to fall during the first trimester of pregnancy and increase in the later trimesters, peaking at 28 to 32 weeks' 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.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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