Insulin Nph + Insulin Regular

Pharmacologic Category

Insulin, Combination

Dosing: Adult

Note: Insulin NPH and insulin regular combination consists of an intermediate-acting insulin (NPH) and a short-acting insulin (regular). With combination insulin products, the proportion of short-acting to long-acting insulin is fixed; basal vs prandial dose adjustments cannot be made. Because of variability in the peak effect and individual patient variability in activities, meals, etc, it may be more difficult to achieve complete glycemic control using fixed combinations of insulins.

Diabetes mellitus, type 1: SubQ:

General insulin dosing: Note: Use of premixed insulin is not generally recommended in type 1 diabetes. Most patients should be treated with multiple daily injections of prandial and basal insulin or continuous subcutaneous insulin infusion (CSII) (ADA 2019; Peters 2013). The total daily doses (TDD) presented below are expressed as the total units/kg/day of all insulin formulations combined.

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/ACE [Handelsman 2015]; ADA 2019).

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

Dosage adjustment: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Note: If using insulin NPH and insulin regular combination, the TDD is typically divided into 2 doses. Given the fixed proportion of individual components in premixed insulin combination products, independent adjustment of the basal or prandial component is not possible. Therefore, use of premixed insulins should be reserved for patients unwilling to take more than two daily doses of insulin and unable to mix individual insulins. In these patients, consistent carbohydrate intake at each meal is essential (Peters 2013).

Diabetes mellitus, type 2: SubQ: Note: Initiation of premixed insulin is an option if adequate glycemic control has not been achieved with other injectable therapy including a GLP-1 receptor agonist and/or basal insulin (± prandial insulin) (ADA 2019).

Initial: If insulin naive, administer 0.3 units/kg/day or 10 to 12 units/day in 2 or 3 divided doses or if converting from other insulin therapy, administer the current total daily insulin dose in 2 or 3 divided doses (dose may require adjustment based on individual patient needs) (ADA 2019).

Dosage adjustment: Individualize dose adjustment based on type of biphasic insulin used; adjustment may be more complex with three-times-daily regimen. Risk of hypoglycemia is greater given the fixed proportion of individual components (ADA 2019).

In patients who develop hypoglycemia (without clear reason), dosage reductions of 10% to 20% have been recommended for basal and prandial insulins (as individual components); in cases of severe hypoglycemia (requiring assistance from another person or blood glucose <40 mg/dL) dosage reductions of 20% to 40% have been recommended (AACE/ACE [Garber 2019]; ADA 2019).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment: Adult

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: Adult

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: Pediatric

Insulin NPH is an intermediate-acting insulin and regular insulin is a short-acting insulin; the combination product is not intended for initial therapy; basal insulin requirements should be established first to direct dosing of the combination insulin products. Because of variability in the peak effect and individual patient variability in activities, meals, etc., it may be more difficult to achieve complete glycemic control using fixed combinations of insulins; frequent monitoring and close medical supervision may be necessary. Premixed insulins are not recommended for routine use in pediatric patients; the proportion of short-acting to intermediate-acting insulin is fixed in the combination products; basal vs prandial dose adjustments cannot be made; premixed insulins may be useful when adherence is an issue (AACE/ACE [Handelsman 2015]; Beck 2015; ISPAD [Danne 2018]). Insulin regimens vary widely by region, practice, and institution; consult institution-specific guidelines.

Type 1 diabetes mellitus: Children and Adolescents: Note: Fixed ratio insulins (such as insulin NPH and insulin regular combination) are typically administered as 2 daily doses with each dose intended to cover 2 meals and a snack.

General insulin dosing: The daily doses presented are expressed as the total units/kg/day of all insulin formulations combined. Premixed insulin is not recommended for routine use in pediatric patients; may be useful when adherence is an issue (Beck 2015; ISPAD [Danne 2018]).

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 of anticipated needs may be 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

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. With combination insulin products, the proportion of rapid-acting to long-acting insulin is fixed; basal vs prandial dose adjustments cannot be made.

Type 2 diabetes mellitus: Children ≥10 years and Adolescents: SubQ: 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]). Insulin NPH and insulin regular combination product is not intended for initial therapy; basal insulin requirements should be established first to direct dosing of combination insulin products. Note: Patients who are ketotic or present with ketoacidosis require aggressive management as indicated.

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

Use: Off-Label: Adult

Gestational diabetes mellitus (GDM)Level 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 ^Ref.

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

Insulin NPH and insulin regular combination products are administered by SubQ injection, typically in 2 divided doses/day with each dose intended to cover two meals or a meal and a snack; administer ~30 to 45 minutes before a meal. Administer into the thigh, upper arm, buttocks, or abdomen; 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 ten times; Humulin 70/30 KwikPen should be rolled between the palms ten times and inverted 180° ten times, Novolin 70/30 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 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, if the insulin remains clear after adequate mixing, or if white particles are stuck to the bottom or wall of the container. Cold injections should be avoided. Do not administer IM or IV, or in an insulin pump. Do not mix with any other insulin formulation or diluents.

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 70/30 KwikPen) or 6 (Novolin 70/30 FlexPen) after the dose dial has returned to 0 units before removing the needle to ensure the full dose has been administered. When there are <12 units remaining in Novolin 70/30 FlexPen replace it with a new one to ensure even mixing.

Administration: Pediatric

SubQ: For subcutaneous administration into the thigh, upper arm, buttocks, or abdomen; Not for IV or IM administration or use in an insulin pump. Rotate injection sites within the same region to reduce the risk of lipodystrophy. Properly resuspended insulin 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, if the insulin remains clear after adequate mixing, or if white particles are stuck to the bottom or wall of the container. Cold injections should be avoided. Administer within 30 to 45 minutes before a meal (before breakfast and supper). Do not mix or dilute with other insulins.

Vials: In order to properly resuspend the insulin, gently roll between the palms at least 10 times and/or carefully invert at least 10 times.

Humulin 70/30 KwikPen: In order to properly resuspend the insulin, roll the pen between the palms 10 times and invert 180° 10 times. 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 keeping the button pressed the entire time and then remove the needle. Check to see if there is a 0 in the dose window, which indicates that the full dose has been administered. If there is no 0 in the dose window, insert needle into the skin and finish injection. Do not redial.

Novolin 70/30 FlexPen: In order to properly resuspend the insulin, invert the pen 180° 20 times prior to the first injection and 10 times thereafter prior to each injection. 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 6 keeping the button pressed the entire time and then remove the needle. Do not rub the area. When there are <12 units remaining in Novolin 70/30 FlexPen, replace it with a new one to ensure even mixing.

Novolin ge Penfill Cartridge [Canadian product]: Prior to insertion into the delivery device (before first use), the cartridge should be rolled between the palms 10 times and then carefully inverted 180° 10 times; see product labeling for specific instructions on inserting the cartridge into the pen delivery device. For subsequent injections, the insulin delivery device (containing cartridge) should be carefully inverted 180° at least 10 times in order to properly resuspend the insulin prior to each injection. 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 6 keeping the button depressed the entire time and then remove the needle. When there are <12 units remaining in the cartridge, replace it with a new one to ensure even mixing.

Dietary Considerations

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

Storage/Stability

Humulin 70/30:

Vials: Store unopened vials in refrigerator between 2°C and 8°C (36°F to 46°F) or at room temperature below 30°C (86°F). If stored at room temperature, the vial must be discarded after 31 days. Do not freeze; discard if frozen. 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).

KwikPen: Store unopened pen in a refrigerator between 2°C and 8°C (36°F to 46°F) or at room temperature below 30°C (86°F); if stored at room temperature, then unopened pen must be discarded after 10 days. Do not freeze; discard if frozen. Keep away from heat and sunlight. Once punctured (in use), pen should be stored at room temperature below 30°C (86°F) for up to 10 days; do not refrigerate in-use pens.

Novolin 70/30:

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; discard if frozen. Keep away from heat and sunlight. Once punctured (in use), store vials at room temperature ≤25°C (≤77°F) for up to 42 days; do not refrigerate in-use vials.

FlexPen: Store unopened pens in 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 up to 28 days. Do not freeze; discard if frozen. Keep away from heat and sunlight. Once in use, store pens at room temperature ≤30°C (≤86°F) for up to 28 days; do not refrigerate in-use pens.

Canadian products: 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; discard if frozen. 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

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.

• Anxiety

• Vision changes

• Chills

• Severe dizziness

• Passing out

• Mood changes

• Seizures

• Slurred speech

• Shortness of breath

• Excessive weight gain

• 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 any component of the formulation; during episodes of hypoglycemia

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.

• 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 at least 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 vs 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 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 (NPO), 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. Premixed insulin formulations should generally be avoided in hospitalized patients due to frequent changes in nutritional status, and an increased risk of hypoglycemia when premixed insulin is given in patients who are NPO or not eating. 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, 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 and insulin regular combination products are NOT intended for IV or IM administration or administration in an insulin infusion pump.

• Appropriate use: Not recommended for treatment of diabetic ketoacidosis (Kitabchi 2009).

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

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). Also refer to individual monographs for additional information.

Breast-Feeding Considerations

Both exogenous and endogenous insulin are excreted into 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 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
• Insulin Regular

Briggs' Drugs in Pregnancy & Lactation

• Insulin

Adverse Reactions

See individual agents. Frequency not defined.

Cardiovascular: Peripheral edema

Dermatologic: Pruritus

Endocrine & metabolic: Hypoglycemia, hypokalemia, weight gain

Hypersensitivity: Hypersensitivity reaction

Immunologic: Immunogenicity

Local: Hypertrophy at injection site, lipoatrophy at injection site

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]); renal function, hepatic function, weight.

Gestational diabetes mellitus: Blood glucose 4 times daily (1 fasting and 3 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 of age) (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 2019):

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 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. Discuss appropriate procedure for when to seek medical attention with symptomatic hypoglycemic episodes.

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, paying special attention to home pen usage. 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.

Product Availability

Novolin 70/30 FlexPen: FDA approved June 2018; anticipated availability is currently unknown.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, suspension:

HumuLIN 70/30: Insulin NPH suspension 70% [intermediate acting] and insulin regular solution 30% [short acting]: 100 units/mL (3 mL, 10 mL) [vial]

HumuLIN 70/30 KwikPen: Insulin NPH suspension 70% [intermediate acting] and insulin regular solution 30% [short acting]: 100 units/mL (3 mL)

NovoLIN 70/30: Insulin NPH suspension 70% [intermediate acting] and insulin regular solution 30% [short acting]: 100 units/mL (10 mL) [vial]

NovoLIN 70/30 FlexPen: Insulin NPH suspension 70% [intermediate acting] and insulin regular solution 30% [short acting]: 100 units/mL (3 mL) [vial]

NovoLIN 70/30 FlexPen Relion: Insulin NPH suspension 70% [intermediate acting] and insulin regular solution 30% [short acting]: 100 units/mL (3 mL) [vial]

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, suspension:

Novolin ge 30/70: Insulin regular solution 30% [short acting] and insulin NPH suspension 70% [intermediate acting]: 100 units/mL (3 mL) [prefilled syringe or PenFill prefilled cartridge]; (10 mL) [vial]

Novolin ge 40/60: Insulin regular solution 40% [short acting] and insulin NPH suspension 60% [intermediate acting]: 100 units/mL (3 mL) [PenFill prefilled cartridge]

Novolin ge 50/50: Insulin regular solution 50% [short acting] and insulin NPH suspension 50% [intermediate acting]: 100 units/mL (3 mL) [PenFill prefilled cartridge]

Anatomic Therapeutic Chemical (ATC) Classification

• A10AD

Generic Available (US)

No

Pricing: US

Suspension (HumuLIN 70/30 Subcutaneous)

(70-30) 100 units/mL (per mL): $17.84

Suspension (NovoLIN 70/30 ReliOn Subcutaneous)

(70-30) 100 units/mL (per mL): $16.52

Suspension (NovoLIN 70/30 Subcutaneous)

(70-30) 100 units/mL (per mL): $16.52

Suspension Pen-injector (HumuLIN 70/30 KwikPen Subcutaneous)

(70-30) 100 units/mL (per mL): $37.70

Suspension Pen-injector (NovoLIN 70/30 FlexPen Relion Subcutaneous)

(70-30) 100 units/mL (per mL): $20.82

Suspension Pen-injector (NovoLIN 70/30 FlexPen Subcutaneous)

(70-30) 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) and insulin regular is an intermediate-acting combination insulin product with a more rapid onset than that of insulin NPH alone.

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: 0.5 hours

Peak effect: 2 to 12 hours

Duration: 18 to 24 hours

Time to peak, plasma: Based on individual components:

Insulin regular: 0.8 to 2 hours

Insulin NPH: 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 NPH
• Insulin Products

Index Terms

Hum Insulin Nph/Reg Insulin Hm; Insulin Regular and Insulin NPH; Isophane Insulin and Regular Insulin; NPH Insulin and Regular Insulin; Regular Insulin and NPH Insulin

FDA Approval Date

April 25, 1989

References

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American College of Obstetricians and Gynecologists (ACOG). ACOG Practice Bulletin No. 201: Pregestational diabetes mellitus. Obstet Gynecol. 2018;132(6):e228-e248. doi: 10.1097/AOG.0000000000002960.[PubMed 30461693]

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.

American Diabetes Association (ADA). Diabetes Care. 2019;42(suppl 1):S1-S193. http://care.diabetesjournals.org/content/42/Supplement_1. Accessed January 10, 2019.

American Diabetes Association (ADA). Standards of medical care in diabetes–2020. Diabetes Care. 2020;43(suppl 1):S1-S212. https://care.diabetesjournals.org/content/43/Supplement_1. Accessed January 22, 2020.

Apovian CM, Aronne LJ, Bessesen DH, et al; Endocrine Society. Pharmacological management of obesity: an Endocrine Society clinical practice guideline [published correction appears in J Clin Endocrinol Metab. 2015;100(5):2135-2136]. J Clin Endocrinol Metab. 2015;100(2):342-362. doi: 10.1210/jc.2014-3415.[PubMed 25590212]

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Chiang JL, Kirkman MS, Laffel LM, Peters 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.[PubMed 24935775]

Copeland KC, Silverstein J, Moore KR, et al. Management of newly diagnosed type 2 diabetes mellitus (T2DM) in children and adolescents [published correction appears in Pediatrics. 2013;131(5):1014]. Pediatrics. 2013;131(2):364-382.[PubMed 23359574]

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Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) [published online October 4, 2018]. Diabetes Care. 2018. pii: dci180033.[PubMed 30291106]

Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm - 2019 executive summary [published correction appears in Endocr Pract. 2019;25(2):204]. Endocr Pract. 2019;25(1):69-100. doi: 10.4158/CS-2018-0535.[PubMed 30742570]

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Humulin 70/30 (70% human insulin isophane suspension and 30% human insulin injection [rDNA origin] suspension) [prescribing information]. Indianapolis, IN: Eli Lilly and Company; November 2019.

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

International Diabetes Federation, International Society for Pediatric and Adolescent Diabetes. Global IDF/ISPAD Guideline for Diabetes in Childhood and Adolescence. 2011. Available at http://www.idf.org/e-library/guidelines/80-the-global-idf-ispad-guidelines-for-diabetes-in-childhood-and-adolescence.html. Last accessed: May 2017.

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Korner J, Inabnet W, Febres G, et al. Prospective study of gut hormone and metabolic changes after adjustable gastric banding and Roux-en-Y gastric bypass. Int J Obes (Lond). 2009;33(7):786-795. doi: 10.1038/ijo.2009.79.[PubMed 19417773]

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Mechanick JI, Youdim A, Jones DB, et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient--2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery. Surg Obes Relat Dis. 2013;9(2):159-191. doi: 10.1016/j.soard.2012.12.010.[PubMed 23537696]

Novolin 70/30 (70% human insulin isophane and 30% human insulin) [prescribing information]. Plainsboro, NJ: Novo Nordisk Inc; November 2019.

Novolin ge (insulin regular) [product monograph]. Mississauga, Ontario, Canada: Novo Nordisk Canada Inc; July 2019.

Peterli R, Steinert RE, Woelnerhanssen B, et al. Metabolic and hormonal changes after laparoscopic Roux-en-Y gastric bypass and sleeve gastrectomy: a randomized, prospective trial. Obes Surg. 2012;22(5):740-748. doi: 10.1007/s11695-012-0622-3.[PubMed 22354457]

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Brand Names: International

Actraphane 30 (CZ); Berlinsulin H 30 70 (DE); Gensulin M30 (TH); Glinux 70/30 (MX); Human Initard (IE); Huminsulin 30/70 (IN); Huminsulin 50-50 (IN); Humulin 30 70 (AE, AU, CR, DO, GT, HN, NI, PA, SV); Humulin 30/70 (CY, IT, NZ, PE, SE); Humulin 60/40 (KR); Humulin 70 30 (KW, PK, SA); Humulin 70/30 (BB, BS, BZ, CL, CN, CO, GY, HK, IL, JM, JO, KR, LB, MX, PH, SR, TH, TT, VE, VN); Humulin 80/20 (KR); Humulin 90/10 (KR); Humulin M 70/30 (TR); Humulin M 80/20 (TR); Humulin M3 (IE, LT, PL, SI, SK); Humulin M3 (Mixture 3) (GB); Humulina 30:70 (ES); Humuline 30 70 (BE); Humuline 30/70 (NL); Insugen 30/70 (MY); Insulin Mixtard 30 HM (IL); Insulina Humulin 70/30 (AR); Insuman 25 (IE); Insuman 50 (IE); Insuman Comb (CZ, EE, GB, TZ); Insuman Comb 25 (CH, DE); Insuman Comb 30 (TH, VN); Mikstard (UA); Mixtard 10 (GR, LI); Mixtard 20 (GR, LI); Mixtard 30 (AT, CZ, DK, ES, GR, HU, LB, LI, MT, MY, NZ, RO, SA, SG); Mixtard 30 HM (AE, BH, CI, EG, ET, GH, GM, GN, HK, IQ, IR, JO, KE, KW, LR, LY, MW, QA, RU, TW); Mixtard 40 (GR, LI); Mixtard 50 (AT, DK, GR, HU, LI, MT, RO); Mixtard 50 HM (KW); Ransilun 30/70 (PH); Scilin M30 (PH); Umuline Profil 30 (FR); Winsulin 30/70 (TH); Wosulin 30/70 (PH, TZ); Wosulin 70/30 (BR)

Last Updated 2/20/20