Insulin Isophane

Pharmacologic Category

Insulin, Intermediate-Acting

Dosing: Adult

Note: Insulin NPH is an intermediate-acting insulin formulation. Insulin requirements vary dramatically between patients and dictate frequent monitoring and close medical supervision.

Diabetes mellitus, type 1: SubQ:

Note: Insulin NPH must be used concomitantly with rapid- or short-acting insulins (ie, multiple daily injection regimen). The total daily doses (TDD) presented below are expressed as the total units/kg/day of all insulin formulations combined.

General insulin dosing:

Initial TDD: ~0.4 to 0.5 units/kg/day; conservative initial doses of 0.2 to 0.4 units/kg/day may be considered to avoid the potential for hypoglycemia; higher initial doses may be required in patients who are obese, sedentary, or presenting with ketoacidosis (AACE [Handelsman 2015]; ADA 2019).

Usual TDD maintenance range: 0.4 to 1 units/kg/day in divided doses (ADA 2019).

Division of TDD (multiple daily injections):

Basal insulin: Generally, 40% to 50% of the TDD is given as basal insulin (intermediate- or long-acting) (AACE [Handelsman 2015]; ADA 2019). Insulin NPH may be administered in 2 divided doses daily (either as equally divided doses, or as ~²/₃ of the dose before the morning meal and ~¹/₃ of the dose before the evening meal or at bedtime). Alternatively, dividing insulin NPH into 3 or 4 doses per day may reduce hypoglycemic risk and establish more consistent basal insulin profile (Peters 2013).

Prandial insulin: The remaining portion (ie, 50% to 60%) of the TDD is then divided and administered before or at mealtimes (depending on the formulation) as a rapid-acting (eg, aspart, glulisine, lispro; insulin for inhalation) or short-acting (regular) insulin (AACE [Handelsman 2015]; ADA 2019).

Dosage adjustment: 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. To minimize hypoglycemia risk, basal insulins are generally titrated once or twice weekly (eg, every 3 or 7 days) (ADA 2019; McCall 2012).

Diabetes mellitus, type 2: SubQ: Note: Basal insulin therapy is usually initiated if adequate glycemic control has not been achieved with step-wise trials of metformin ± other noninsulin agents. However, if HbA_1c ≥10%, blood glucose is ≥300 mg/dL or if patient is symptomatic (eg, polyuria, polydipsia), insulin (with or without additional agents) should be considered as part of initial therapy. Use of long-acting basal analogs may be preferred if minimization of hypoglycemia is a primary concern (AACE/ACE [Garber 2019]; ADA 2019).

Initial: 0.1 to 0.2 units/kg/day or 10 units/day administered in 1 or 2 divided doses (ADA 2019; Lipska 2017).

Dosage adjustment (AACE/ACE [Garber 2019]; ADA 2019):

To reach self-monitoring glucose target: Adjust dose by 2 units every 3 days to reach fasting plasma glucose target while avoiding hypoglycemia.

For hypoglycemia: If no clear reason for hypoglycemia, decrease dose by 10% to 20%; for severe hypoglycemia (ie, requiring assistance from another person or blood glucose <40 mg/dL) reduce dose by 20% to 40%.

Dosage adjustment when adding prandial insulin (ADA 2019): Consider reducing the basal insulin dose by 4 units (or ~10%) if HbA_1c is <8% when initiating prandial insulin.

Patients with diabetes receiving enteral feedings (ADA 2019): Note: TDD of insulin is divided into a basal component (intermediate- or long-acting insulin) and nutritional and correctional components (regular insulin or rapid-acting insulins).

Basal component: SubQ: Continue previous basal insulin dose or administer 30% to 50% of TDD as insulin NPH; if basal insulin naive, administer insulin NPH 5 units every 12 hours.

Patients with diabetes undergoing surgery (ADA 2019): On the morning of surgery or procedure, give 50% of the usual dose of insulin NPH.

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment: Adult

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: Adult

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: Adult

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

Dosing: Pediatric

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 doses should be individualized based on patient needs; adjustments may be necessary with changes in physical activity, meal patterns, acute illness, or with changes in renal or hepatic function. Insulin requirements vary dramatically between patients and dictate frequent monitoring and close medical supervision. Insulin regimens vary widely by region, practice, and institution; consult institution-specific guidelines.

Type 1 diabetes mellitus: Children and Adolescents: Note: For basal insulin coverage, long-acting insulin analogs are preferred over insulin NPH due to decreased risk of hypoglycemia (AACE/ACE [Handelsman 2015]; ADA 2018; ADA [Chiang 2014]). The daily doses presented are expressed as the total units/kg/day of all insulin formulations combined.

Initial total daily insulin: SubQ:Initial: 0.4 to 0.5 units/kg/day in divided doses (AACE/ACE [Handelsman 2015]; ADA 2018); usual range: 0.4 to 1 units/kg/day in divided doses (AACE/ACE [Handelsman 2015; ADA 2018; Silverstein 2005); lower doses (0.25 units/kg/day) may be used especially in young children to avoid potential hypoglycemia (Beck 2015); higher doses may be necessary for some patients (eg, obese, concomitant steroids, puberty, sedentary lifestyle, following diabetic ketoacidosis presentation) (AACE/ACE [Handelsman 2015]; ADA 2018)

Usual total daily maintenance range: SubQ: Doses must be individualized; however, an estimate can be determined based on phase of diabetes and level of maturity (ISPAD [Danne 2018]; ISPAD [Sundberg 2017]):

Partial remission phase (Honeymoon phase): <0.5 units/kg/day

Prepubertal children (not in partial remission):

Infants ≥6 months and Children ≤6 years: 0.4 to 0.8 units/kg/day

Children ≥7 years: 0.7 to 1 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

Division of daily insulin requirement (multiple daily injections):

Basal insulin: Generally, ~30% to 50% of the total daily insulin is given as basal insulin (intermediate- or long-acting) (AACE/ACE [Handelsman 2015]; ADA 2018; ISPAD [Danne 2018]; Peters 2013). When utilizing a twice daily NPH regimen, ~50% to 60% of the total daily insulin administered as NPH has been recommended with more (~²/₃) of the total daily insulin administered in the morning and less (~¹/₃) of the total daily dose administered in the evening or at bedtime (ISPAD [Danne 2014]). Dividing the total daily dose of insulin NPH into 3 or 4 doses per day may reduce hypoglycemic risk and establish a more consistent basal insulin profile (Peters 2013).

Prandial insulin: The remaining portion of the total daily dose is then divided and administered before or at mealtimes (depending on the formulation) as rapid-acting (eg, aspart, glulisine, lispro) or short-acting (regular). In most type 1 patients, the use of a rapid-acting insulin analog is preferred over regular insulin to reduce hypoglycemia risk (AACE/ACE [Handelsman 2015]; ADA 2018; ADA [Chiang 2014]; ISPAD [Danne 2018]).

Dose titration: Treatment and monitoring regimens must be individualized to maintain premeal and bedtime glucose in target range, titrate dose 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.

Patients receiving enteral/parenteral feedings: Data is limited in pediatric patients; in adults, the following is recommended: Bolus or continuous enteral feedings: SubQ: Continue previous basal insulin dose or if basal insulin naive, administer 30% to 50% of total daily dose of insulin received while being fed as insulin NPH (ADA 2018); administer in conjunction with nutritional and correctional insulin dosing with a rapid-acting or regular insulin.

Surgical patients (ISPAD [Jefferies 2018]): Note: Diabetic patients should be scheduled as the first case of the day.

Minor surgeries:

Morning procedure: Administer 50% to 70% of the usual morning dose of insulin NPH OR administer IV insulin (regular) infusion; begin IV fluids containing dextrose; in general rapid acting insulin should be omitted until after surgery and patient is able to eat unless it is needed to correct significant hyperglycemia and/or significant ketone (>0.1 mmol/mol) production is present.

Afternoon procedure: Administer 70% to 100% of the usual morning dose of insulin NPH depending on the amount of breakfast allowed.

Postprocedure: Once normal oral intake is achieved, resume usual insulin regimen; monitor closely due to risk of changes related to surgery (postoperative stress, medication changes, inactivity)

Major surgeries: Omit morning insulin (short and long acting) and start IV insulin (regular) infusion and IV dextrose; patients on continuous subcutaneous insulin infusion should discontinue CSII when IV insulin infusion is started; once normal oral intake is resumed, then resume usual insulin regimen; monitor closely due to risk of changes related to surgery (postoperative stress, medication changes, inactivity)

Type 2 diabetes mellitus: Limited data available: Note: The goal of therapy is to achieve an HbA_1c <7% as quickly as possible using the safe titration of medications. Initial therapy in metabolically unstable patients (eg, plasma glucose ≥250 mg/dL, HbA_1c >9% and symptoms excluding acidosis) may include once daily intermediate-acting insulin or basal insulin in combination with lifestyle changes and metformin. In patients who fail to achieve glycemic goals with metformin and basal insulin, may consider initiating prandial insulin (regular insulin or rapid acting insulin) and titrate to achieve goals. Once initial goal reached, insulin should be slowly tapered over 2 to 6 weeks by decreasing the insulin dose by 10% to 30% every few days and the patient transitioned to lowest effective doses or metformin monotherapy if able (AAP [Copeland 2013]; ADA 2018; ISPAD [Zeitler 2018]).

Children ≥10 years and Adolescents with ketosis/ketoacidosis/ketonuria: SubQ: Initial: 0.25 to 0.5 units/kg/dose once daily; use in in combination with lifestyle changes and metformin to achieve goals (ISPAD [Zeitler 2018])

Dosing: Renal Impairment: Pediatric

There are no dosage adjustments 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: Pediatric

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

Use: Labeled Indications

Diabetes mellitus, types 1 and 2: Treatment of types 1 and 2 diabetes mellitus to improve glycemic control in adults and pediatric patients

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Gestational diabetes mellitusLevel of Evidence [G]

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.

Level of Evidence Definitions

Level of Evidence Scale

Class and Related Monographs

Insulin

Clinical Practice Guidelines

Diabetes Mellitus:

American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE), “Consensus Statement on the Comprehensive Type 2 Diabetes Management Algorithm - 2019 Executive Summary,” January 2019

American Diabetes Association, “Standards of Medical Care in Diabetes - 2019,” January 2019

American Diabetes Association and the European Association for the Study of Diabetes Consensus Report, “Management of Hyperglycemia in Type 2 Diabetes, 2018,” December 2018

Diabetes Canada, “Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada,” 2018

Administration: Subcutaneous

For subcutaneous administration into the thigh, upper arm, buttocks, or abdomen; do not administer IM or IV, or in an insulin pump. Absorption rates vary amongst injection sites; be consistent with area used while rotating injection sites within the same region to reduce the risk of lipodystrophy or localized cutaneous amyloidosis. Rotating from an injection site where lipodystrophy/cutaneous amyloidosis is present to an unaffected site may increase risk of hypoglycemia.

In order to properly resuspend the insulin, vials should be carefully inverted or rolled at least 10 times. Humulin N KwikPen should be rolled between the palms ten times and inverted 180° ten times, and Novolin N FlexPen should be inverted 180° twenty times prior to the first injection and ten times thereafter. 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. When there are less than 12 units remaining in Novolin N FlexPen, replace it with a new one to ensure even mixing.

For prefilled pens, prime the needle before each injection with 2 units of insulin. Once injected, hold the needle in the skin for a count of 5 (Humulin N KwikPen) or 6 (Novolin N FlexPen) after the dose dial has returned to 0 units before removing the needle to ensure the full dose has been administered.

Administration: Pediatric

SubQ: Administer subcutaneously into the thigh, upper arm, buttocks, or abdomen; do not administer IM, 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. Humulin N KwikPen should be rolled between the palms 10 times and inverted 180° 10 times, and Novo N FlexPen should be inverted 180° 20 times prior to the first injection and 10 times thereafter. 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.

For prefilled pens, prime the needle before each injection with 2 units of insulin; see manufacturer's labeling for specific procedure. Once primed, set dial to the appropriate dose, insert needle into clean skin, and activate device; once insulin is injected, hold the needle in the skin for a count of 5 (Humulin N KwikPen) or 6 (Novolin N FlexPen) after the dose dial has returned to 0 units to ensure the full dose has been administered before removing the needle. If dose is >60 units, more than 1 injection will be required; split dose and administer in multiple injections.

Dietary Considerations

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

Storage/Stability

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 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; refrigeration of in-use vials is not recommended.

Novolin N FlexPen: Store unopened pen in the refrigerator between 2°C and 8°C (36°F to 46°F) until product expiration date or at room temperature <30°C (<86°F) for 28 days; do not freeze; keep away from heat and sunlight. Once punctured (in use), store <30°C (<86°F) for up to 28 days; refrigeration of in-use pens 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.

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to lower blood sugar in patients with high blood sugar (diabetes).

Frequently reported side effects of this drug

• Injection site irritation

• Weight gain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating.

• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat.

• Vision changes

• Burning or numbness feeling

• Severe dizziness

• Passing out

• Mood changes

• Seizures

• Slurred speech

• Swelling of arms or legs

• Injection site thick skin, pits, or lumps

• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

High alert medication:

Other safety concerns:

Contraindications

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

Documentation of allergenic cross-reactivity for drugs in this class is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Warnings/Precautions

Concerns related to adverse effects:

• Glycemic control: Hyper- or hypoglycemia may result from changes in insulin strength, manufacturer, type, and/or administration method. The most common adverse effect of insulin is hypoglycemia. The timing of hypoglycemia differs among various insulin formulations. Hypoglycemia may result from changes in meal pattern (eg, macronutrient content, timing of meals), changes in the level of physical activity, increased work or exercise without eating, or changes to coadministered medications. Use of long-acting insulin preparations (eg, insulin degludec, insulin detemir, insulin glargine) may delay recovery from hypoglycemia. Patients with renal or hepatic impairment may be at a higher risk. Symptoms differ in patients and may change over time in the same patient; awareness may be less pronounced in those with long-standing diabetes, diabetic nerve disease, patients taking beta-blockers, or in those who experience recurrent 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. In clinical trials insulin NPH has been associated with a modestly increased risk of hypoglycemia (including nocturnal hypoglycemia) compared with long-acting analogs (Lipska 2017; Rosenstock 2005; Rys 2015; Singh 2009). However, an observational study in patients with type 2 diabetes from a large health care delivery system found no difference in the incidence of ER visits or hospitalization for hypoglycemia with NPH compared with glargine/detemir when treating to conventional targets in a real world setting (Lipska 2018).

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

• 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:

• Bariatric surgery:

– Type 2 diabetes, hypoglycemia: Closely monitor insulin dose requirement throughout active weight loss with a goal of eliminating antidiabetic therapy or transitioning to agents without hypoglycemic potential; hypoglycemia after gastric bypass, sleeve gastrectomy, and gastric band may occur (Mechanick 2013). Insulin secretion and sensitivity may be partially or completely restored after these procedures (Korner 2009; Peterli 2012). Rates and timing of type 2 diabetes improvement and resolution vary widely by patient. Insulin dose reduction of ≥75% has been suggested after gastric bypass for patients without severe β-cell failure (fasting c-peptide <0.3 nmol/L) (Cruijsen 2014). Avoid the use of bolus insulin injections or dose conservatively with close clinical monitoring in the early phases after surgery.

– Weight gain: Evaluate risk versus benefit and consider alternative therapy after gastric bypass, sleeve gastrectomy, and gastric banding; weight gain may occur (Apovian 2015).

• Cardiac disease: Concurrent use with peroxisome proliferator-activated receptor (PPAR)-gamma agonists, including thiazolidinediones (TZDs) may cause dose-related fluid retention and lead to or exacerbate heart failure, particularly when used in combination with insulin. If PPAR-gamma agonists are prescribed, monitor for signs and symptoms of heart failure. If heart failure develops, consider PPAR-gamma agonist dosage reduction or therapy discontinuation.

• 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 2019).

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.

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

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

Intensive glucose control (HbA_1c <6.5%) has been linked to increased all-cause and cardiovascular mortality, hypoglycemia requiring assistance, and weight gain in adult type 2 diabetes. How "tightly" to control a geriatric patient's blood glucose needs to be individualized. Such a decision should be based on several factors, including the patient's functional and cognitive status, how well he/she recognizes hypoglycemic or hyperglycemic symptoms, and how to respond to them and other disease states. An HbA_1c <7.5% is an acceptable endpoint for a healthy older adult, while <8% is acceptable for frail elderly patients, those with a duration of illness >10 years, or those with comorbid conditions and requiring combination diabetes medications. In patients with advanced microvascular complications and/or a life expectancy <5 years, a target HbA_1c of 8% to 9% is reasonable. Patients who are unable to accurately draw up their dose will need assistance, such as prefilled syringes. Initial doses may require considerations for renal function in the elderly with dosing adjusted subsequently based on blood glucose monitoring. For elderly patients with diabetes who are relatively healthy, attaining target goals for aspirin use, blood pressure, lipids, smoking cessation, and diet and exercise may be more important than normalized glycemic control.

Pregnancy Considerations

Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia (ACOG 201 2018). To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA_1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2020; Blumer 2013).

Due to pregnancy-induced physiologic changes, insulin requirements tend to increase as pregnancy progresses, requiring frequent monitoring and dosage adjustments. Following delivery, insulin requirements decrease rapidly (ACOG 201 2018; ADA 2020).

Insulin is the preferred treatment of type 1 and type 2 diabetes mellitus in pregnancy, as well as gestational diabetes mellitus, when pharmacologic therapy is needed (ACOG 190 2018; ACOG 201 2018; ADA 2020). NPH insulin may be used to treat diabetes mellitus in pregnancy (ACOG 190 2018; ACOG 201 2018; Blumer 2013)

Breast-Feeding Considerations

Both exogenous and endogenous insulin are present in breast milk (study not conducted with this preparation) (Whitmore 2012).

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.

Breastfeeding is encouraged for all females, including those with type 1, type 2, or gestational diabetes mellitus (ACOG 201 2018; ADA 2020; Blumer 2013). A small snack before breastfeeding may help decrease the risk of hypoglycemia in females with pregestational diabetes (ACOG 201 2018; Reader 2004).

Lexicomp Pregnancy & Lactation, In-Depth

• Insulin NPH

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

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Insulin Preparation Allergy

Toxicology

• Insulins

Metabolism/Transport Effects

None known.

Drug Interactions Open Interactions

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

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

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

Beta-Blockers: May enhance the hypoglycemic effect of Insulins. Exceptions: Levobunolol; Metipranolol. Risk C: 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. Risk D: Consider therapy modification

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Edetate CALCIUM Disodium: May enhance the hypoglycemic effect of Insulins. Risk C: 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. Exceptions: Liraglutide. Risk D: Consider therapy modification

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

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

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

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

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: 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). Risk D: Consider therapy modification

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

Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

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. Risk D: Consider therapy modification

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

Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: 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. Risk D: 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. Risk D: Consider therapy modification

Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

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

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: 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. Risk X: Avoid combination

Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

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

Sodium-Glucose Cotransporter 2 (SGLT2) 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. Risk D: Consider therapy modification

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

Monitoring Parameters

Diabetes mellitus: Plasma glucose (typically before meals and snacks and at bedtime; occasionally additional monitoring may be required), electrolytes, HbA_1c (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 2019]); lipid profile, renal function, hepatic function, weight

Gestational diabetes mellitus: Blood glucose 4 times daily (one fasting and three postprandial) until well controlled, then as appropriate (ACOG 190 2018).

Reference Range

Recommendations for glycemic control in patients with diabetes:

Nonpregnant adults (ADA 2019):

HbA_1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA_1c goal may be targeted based on patient-specific characteristics)

Preprandial capillary blood glucose: 80 to 130 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics)

Peak postprandial capillary blood glucose: <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics)

Older adults (≥65 years) (ADA 2019):

HbA_1c: <7.5% (healthy); <8% (complex/intermediate health); <8.5% (very complex/poor health) (individualization may be appropriate based on patient and caregiver preferences)

Preprandial capillary blood glucose: 90 to 130 mg/dL (healthy); 90 to 150 mg/dL (complex/intermediate health); 100 to 180 mg/dL (very complex/poor health)

Bedtime capillary blood glucose: 90 to 150 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health)

Pregnant patients:

HbA_1c: Pregestational diabetes (type 1 or type 2) (ADA 2019):

Preconception (patients planning for pregnancy): <6.5%

During pregnancy <6% (if can be achieved without significant hypoglycemia) or <7% if needed to prevent hypoglycemia

Capillary blood glucose: Pregestational diabetes mellitus (type 1 or type 2) (ADA 2019) or gestational diabetes mellitus (ACOG 190 2018) (less stringent targets may be appropriate if goals cannot be achieved without causing significant hypoglycemia):

Fasting: <95 mg/dL

Postprandial: <140 mg/dL (at 1 hour) or <120 mg/dL (at 2 hours)

Pediatric (all age groups) patients with type 1 diabetes (ADA 2018):

HbA_1c: <7.5% (individualization may be appropriate based on patient-specific characteristics; <7% is reasonable if it can be achieved without excessive hypoglycemia)

Preprandial capillary blood glucose: 90 to 130 mg/dL

Bedtime and overnight capillary blood glucose: 90 to 150 mg/dL

Hospitalized adult patients (ADA 2019): Target glucose range: 140 to 180 mg/dL (majority of critically ill and noncritically ill patients; <140 mg/dL may be appropriate for selected patients, if it can be achieved without excessive hypoglycemia). Initiate insulin therapy for persistent hyperglycemia at ≥180 mg/dL

Perioperative care in adult patients (ADA 2019): Target glucose range during perioperative period: Consider targeting 80 to 180 mg/dL

Classification of hypoglycemia (ADA 2019):

Level 1: ≥54 to ≤70 mg/dL; hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment

Level 2: <54 mg/dL; threshold for neuroglycopenic symptoms; requires immediate action

Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance

Advanced Practitioners Physical Assessment/Monitoring

Obtain HbA1c (at least twice annually if meeting goals and quarterly for patients not meeting treatment goals or with therapy change), serum glucose, electrolytes, renal function tests, and liver function tests. Monitor closely blood glucose and serum potassium in patients receiving IV administration. Monitor weight. Monitor for hypoglycemia at regular intervals during therapy. Teach patient proper use, including appropriate injection technique and syringe/needle disposal, and monitoring requirements. Refer to dietician and/or diabetes self-management education.

Nursing Physical Assessment/Monitoring

Check ordered labs and report abnormalities. Monitor for hypoglycemia at regular intervals during therapy. Teach patient proper use, including appropriate injection technique and syringe/needle disposal, and monitoring requirements. Educate and instruct patient to report signs of hypoglycemia (dizziness, headache, fatigue, weakness, shaking, fast heartbeat, confusion, hunger, or sweating) or hypokalemia (muscle pain or weakness, muscle cramps, or an abnormal heartbeat). May need referral to dietician and/or diabetes self-management education.

Dosage Forms: US

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]

NovoLIN N FlexPen: 100 units/mL (3 mL) [contains metacresol, phenol]

NovoLIN N FlexPen ReliOn: 100 units/mL (3 mL) [contains metacresol, phenol]

Anatomic Therapeutic Chemical (ATC) Classification

• A10AB01

Generic Available (US)

No

Pricing: US

Suspension (HumuLIN N Subcutaneous)

100 units/mL (per mL): $17.84

Suspension (NovoLIN N ReliOn Subcutaneous)

100 units/mL (per mL): $16.52

Suspension (NovoLIN N Subcutaneous)

100 units/mL (per mL): $16.52

Suspension Pen-injector (HumuLIN N KwikPen Subcutaneous)

100 units/mL (per mL): $37.70

Suspension Pen-injector (NovoLIN N FlexPen ReliOn Subcutaneous)

100 units/mL (per mL): $20.82

Suspension Pen-injector (NovoLIN N FlexPen Subcutaneous)

100 units/mL (per mL): $20.82

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

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.

Pharmacodynamics/Kinetics

Note: Onset and duration of hypoglycemic effects depend upon the route of administration (absorption and onset of action are more rapid after deeper IM injections than after SubQ), site of injection (onset and duration are progressively slower with SubQ injection into the abdomen, arm, buttock, or thigh respectively), volume and concentration of injection, and the preparation administered. Rate of absorption, onset, and duration of activity may be affected by exercise, presence of lipodystrophy, local blood supply, and/or temperature.

Onset of action: 1 to 2 hours

Peak effect: 4 to 12 hours

Duration: 14 to 24 hours

Time to peak, plasma: 6 to 10 hours

Excretion: Urine

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: In general, morning appointments are advisable in patients with diabetes since endogenous cortisol levels are typically higher at this time; because cortisol increases blood sugar levels, the risk of hypoglycemia is less. It is important to confirm that the patient has eaten normally prior to the appointment and has taken all scheduled medications. If a procedure is planned with the expectation that the patient will alter normal eating habits ahead of time (eg, conscious sedation), diabetes medication dose may need to be modified in consultation with the patient’s physician. Patients with well-controlled diabetes can usually be managed conventionally for most surgical procedures. Although patients with diabetes usually recognize signs and symptoms of hypoglycemia and self-intervene before changes in or loss of consciousness occurs, they may not. Staff should be trained to recognize the signs (eg, unusual behavior or profuse sweating in patients who have diabetes) and treat patients who have hypoglycemia; a glucometer should be used to test patient blood glucose levels. Every dental office should have a protocol for managing hypoglycemia in conscious and unconscious patients. Having snack foods or oral glucose tablets or gels available, especially in practices where a large number of surgical procedures are performed, is also prudent (American Diabetes Association 2017).

Effects on Bleeding

No information available to require special precautions

Related Information

• Insulin Products

Index Terms

Isophane Insulin; NPH Insulin

FDA Approval Date

October 28, 1982

References

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American Diabetes Association (ADA). Diabetes Care. 2019;42(suppl 1):S1-S193. http://care.diabetesjournals.org/content/42/Supplement_1. Accessed February 8, 2019.

American Diabetes Association (ADA). Standards of medical care in diabetes—2018. Diabetes Care. 2018;41(suppl 1):S1-S159. http://care.diabetesjournals.org/content/41/Supplement_1. Accessed June 18, 2018.

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Chiang JL, Kirkman MS, Laffel LM, et al; Type 1 Diabetes Sourcebook Authors. Type 1 diabetes through the life span: a position statement of the American Diabetes Association. Diabetes Care. 2014;37(7):2034-2054. doi: 10.2337/dc14-1140.[PubMed 24935775]

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Humulin N (human insulin isophane [rDNA origin]) suspension injection [prescribing information]. Indianapolis, IN: Eli Lilly; November 2019.

Humulin N KwikPen (human insulin [rDNA origin] isophane suspension) [prescribing information]. Indianapolis, IN: Eli Lilly; January 2017.

Humulin R, Humulin N, and Humulin 30/70 (insulin isophane, human biosynthetic [rDNA origin]) [product monograph]. Toronto, Ontario, Canada: Eli Lilly Canada Inc; May 2016.

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Brand Names: International

Basal-H-Insulin (DE); Biohulin NPH (KR); Biosulidd N (PH); Gensulin N (TH); Hensulin N (UA); Human Protaphane (GB, IE); Huminsulin "Lilly" Basal (NPH) (AT); Huminsulin Basal (NPH) (CH, DE); Humulin I (IE); Humulin N (AE, AU, BB, BF, BG, BJ, BM, BR, BS, BZ, CI, CO, CY, EE, ET, GH, GM, GN, GY, HK, HR, ID, IL, IQ, IR, IT, JM, JO, KE, KR, KW, LB, LK, LR, LT, LV, LY, MA, ML, MR, MU, MW, MX, MY, NE, NG, NL, OM, PE, PH, PK, PL, PY, RO, SA, SC, SD, SG, SI, SK, SL, SN, SR, SY, TH, TN, TT, TZ, UG, UY, VE, VN, YE, ZA, ZM, ZW); Humulin NPH (DK, GR, SE, TW, UA); Humulina NPH (ES); Humuline NPH (BE); Humullin NPH (IS); Insugen N (MY); Insulatard (CZ, DE, DK, EE, FI, FR, GB, HU, IE, IS, LT, MY, NL, NO, PK, PL, PT, PY, SE, SG, SI, SK, TH, TR, UY, VN); Insulatard HM (AE, AR, AT, BE, BF, BH, BJ, CH, CI, CL, CY, EG, ET, GH, GM, GN, IL, IN, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, PH, SA, SC, SD, SL, SN, SY, TN, TW, TZ, UG, YE, ZA, ZM, ZW); Insulin Protaphane HM (DE); Insulina Humulin (AR, CL); Insuline Humuline NPH (NL); Insuline Isuhuman Basal (NL); Insuman Basal (DE, PH, TH); Insuman N (CR, DO, EC, GT, HN, NI, PA, SV); Jusline N (TZ); Novolet N (KR); Novolin N (CN, JP, KR, MX); Protaphane HM (AE, BF, BJ, CI, CY, EG, ET, GH, GM, GN, HK, IL, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, MY, NE, NG, OM, PH, SA, SC, SD, SL, SN, SY, TH, TN, TZ, UG, YE, ZA, ZM, ZW); Ranisulin-N (PH); SciLin N (CN); Scilin N (HK, PH); Umuline NPH (FR); Umuline Protamine Isophane (FR); Winsulin-N (TH); Wosulin N (TZ); Wosulin-N (PH)

Last Updated 2/25/20