Version May 2024
Note: Insulin aspart protamine and insulin aspart combination consists of a fixed combination of intermediate-acting basal insulin (aspart protamine) and a rapid-acting prandial insulin (aspart). Risk of hypoglycemia may be higher due to less dosing flexibility compared to separate basal and prandial insulin injections (AACE/ACE [Garber 2020]).
Diabetes mellitus, type 1, treatment:
Note: Use of premixed insulin is not generally recommended in patients with type 1 diabetes. Most patients should be treated with multiple daily injections of prandial and basal insulin or continuous SUBQ insulin infusion (ADA 2023; Peters 2013). 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: SUBQ: ~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 with obesity, or who are sedentary or presenting with ketoacidosis (AACE/ACE [Handelsman 2015]; ADA 2023).
Usual TDD maintenance range: SUBQ: 0.4 to 1 units/kg/day in divided doses (typically twice daily if using premixed insulin) (ADA 2023; Peters 2013).
Dosage adjustment: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Given the fixed proportion of insulin aspart protamine and insulin aspart, independent adjustment of each component is not possible. Therefore, use of premixed insulins should be reserved for patients unwilling or unable to take more than two daily doses of insulin or to mix individual insulins. In these patients, consistent carbohydrate intake at each meal is essential (Peters 2013).
Diabetes mellitus, type 2, treatment:
Note: May be used in patients who are on stable doses of basal and prandial insulins or as initial insulin therapy, particularly in patients in whom a simplified insulin regimen is desirable; however, use of premixed insulin is associated with less flexibility in dosage adjustments than separate basal and prandial insulins (AACE/ACE [Garber 2020]; ADA 2023; Wexler 2022). Consider discontinuing noninsulin agents other than metformin, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors (ADA 2023; ADA/EASD [Davies 2018]).
Initial:
Insulin naïve: SUBQ: 0.2 to 0.3 units/kg/day or 10 to 12 units/day in 2 divided doses before meals (eg, two-thirds of the dose before breakfast and one-third of the dose before dinner) (ADA/EASD [Davies 2018]; Wexler 2022). Some experts use a minimum of 10 units/day and do not exceed 20 units/day for the initial dose (Wexler 2022).
Converting from other insulin therapy: SUBQ: Administer the current total daily insulin dose in 2 divided doses before meals (eg, two-thirds of the dose before breakfast and one-third of the dose before dinner); may consider a 20% to 30% dose reduction when initiating premixed insulin (ADA/EASD [Davies 2018]; Wexler 2022; Wu 2015).
Dosage adjustment: Note: Individualize dosage adjustments based on patient-specific factors (eg, glucose levels, carbohydrate intake) (ADA 2023). Given the fixed proportion of basal and prandial insulin, independent adjustment of each component is not possible.
For persistently elevated glucose levels: SUBQ: Consider intensification of dietary modifications and/or increasing individual premixed insulin doses by 2 to 6 units once or twice per week (depending on glucose trends) while avoiding hypoglycemia (ADA 2023; Raskin 2005; Wu 2015).
For hypoglycemia: SUBQ: For unexplained mild to moderate hypoglycemia, consider decreasing daily dose by 10% to 20% (ADA 2023); for severe hypoglycemia requiring assistance from another person or blood glucose <40 mg/dL, consider decreasing daily dose by 20% to 50% (AACE/ACE [Garber 2020]; Wexler 2022).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustment provided in the manufacturer’s labeling; insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely.
There are no dosage adjustment provided in the manufacturer’s labeling; insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely.
Refer to adult dosing.
(For additional information see "Insulin aspart protamine and insulin aspart: Pediatric drug information")
Insulin aspart protamine is an intermediate-acting insulin and insulin aspart is a rapid-acting insulin; the combination product is not intended for initial therapy; basal insulin requirements should be established first to direct dosing of combination insulin products. 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.
Diabetes mellitus, type 1: Limited data available: Note: Fixed ratio insulins (such as insulin aspart protamine and insulin aspart combination) are typically administered as 2 daily doses prior to meals (each dose is intended to cover 2 meals or a meal and a snack) but may be administered 3 times daily with meals if needed (Sheldon 2009). Most patients should be treated with multiple daily injections of prandial and basal insulin or continuous SUBQ insulin infusion (ADA 2023; ISPAD [Sherr 2022]; Peters 2013).
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; the proportion of rapid-acting to long-acting insulin is fixed; basal versus prandial dose adjustments cannot be made; premixed insulin may be useful when adherence is an issue; however, higher rates of diabetic ketoacidosis and severe hypoglycemia risk have been reported in children and adolescents receiving premixed insulins compared to basal-bolus regimens (Beck 2015; ISPAD [Cengiz 2022]).
Children and Adolescents:
Initial total daily insulin: SUBQ: Initial: 0.4 to 0.5 units/kg/day in divided doses (AACE [Blonde 2022]; ADA 2023; Peters 2013); usual range: 0.4 to 1 units/kg/day in divided doses (typically twice daily if using premixed insulin) (ADA 2023; Peters 2013; 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, concomitant steroids, puberty, sedentary lifestyle, obesity, following diabetic ketoacidosis presentation) (AACE [Blonde 2022]; Beck 2015; Peters 2013).
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 [Cengiz 2022]; ISPAD [Sundberg 2022]).
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 unit/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.
Dosage adjustment: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Given the fixed proportion of insulin aspart protamine and insulin aspart, independent adjustment of each component is not possible. Therefore, use of premixed insulins should be reserved for patients unwilling or unable to take more than 2 daily doses of insulin or to mix individual insulins. In these patients, consistent carbohydrate intake at each meal is essential (Peters 2013).
Diabetes mellitus, type 2: Limited data available: Note: Premixed insulins (eg, insulin aspart protamine and insulin aspart combination) are not intended for initial therapy in patients with type 2 diabetes; the proportion of rapid-acting to long-acting insulin is fixed; basal versus prandial dose adjustments cannot be made; premixed insulins may be useful when adherence is an issue. Basal insulin requirements should be established first to direct dosing of combination insulin products. The initiation of a prandial insulin-containing product should be considered if glycemic targets are not achieved with a combination of metformin and basal insulin dose of up to 1.5 units/kg/day (AACE [Blonde 2022]; Beck 2015; ISPAD [Cengiz 2022]; ISPAD [Shah 2022]).
Conversion to premixed insulins: Children ≥10 years and Adolescents: SUBQ: Pediatric-specific data for converting patients from basal and prandial regimens to premixed insulins (such as insulin aspart protamine and insulin aspart combination) do not exist; adult data suggest decreasing insulin dose by 20% to 30% when transitioning to premixed insulins; doses are typically administered as 2 daily doses prior to meals (each dose is intended to cover 2 meals or a meal and a snack) but may be administered 3 times daily with meals if needed (ISPAD [Shah 2022]; Sheldon 2009; Wu 2015; manufacturer's labeling).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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.
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.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Endocrine & metabolic: Hypoglycemia (47% to 75%), severe hypoglycemia (4% to 16%)
Frequency not defined:
Cardiovascular: Peripheral edema
Endocrine & metabolic: Hypokalemia, sodium retention, weight gain
Gastrointestinal: Abdominal pain, diarrhea, dyspepsia
Hypersensitivity: Anaphylaxis, hypersensitivity reaction
Immunologic: Antibody development
Infection: Infection
Local: Hypersensitivity at injection site (including edema, erythema, or pruritus), lipoatrophy at injection site, lipohypertrophy at injection site
Nervous system: Headache, neuropathy
Neuromuscular & skeletal: Back pain, skeletal pain
Respiratory: Flu-like symptoms, pharyngitis, rhinitis, upper respiratory tract infection
Postmarketing: Endocrine & metabolic: Amyloidosis (localized cutaneous at injection site)
Hypersensitivity to insulin aspart protamine, insulin aspart, or any component of the formulation; during episodes of hypoglycemia.
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: Severe, life-threatening hypersensitivity reactions including anaphylaxis may occur with insulin products; discontinue use if hypersensitivity occurs and treat as indicated.
• 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 2020). 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: Insulin therapy is preferred over oral agents (other than metformin) if antidiabetic therapy is required during the perioperative period (Mechanick 2019). Evaluate risk versus benefit of long-term postoperative use and consider alternative therapy due to potential for insulin-induced weight gain (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.
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 2023).
Dosage form specific issues:
• Multiple dose injection pens: According to the 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 aspart protamine and insulin aspart premixed 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.
• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, suspension:
NovoLOG® Mix 70/30: Insulin aspart protamine suspension 70% [intermediate acting] and insulin aspart solution 30% [rapid acting]: 100 units/mL (10 mL)
NovoLOG® Mix 70/30 FlexPen®: Insulin aspart protamine suspension 70% [intermediate acting] and insulin aspart solution 30% [rapid acting]: 100 units/mL (3 mL)
No
Suspension (Insulin Aspart Prot & Aspart Subcutaneous)
(70-30) 100 units/mL (per mL): $8.68
Suspension (NovoLOG Mix 70/30 ReliOn Subcutaneous)
(70-30) 100 units/mL (per mL): $8.68
Suspension (NovoLOG Mix 70/30 Subcutaneous)
(70-30) 100 units/mL (per mL): $8.68
Suspension Pen-injector (NovoLOG 70/30 FlexPen ReliOn Subcutaneous)
(70-30) 100 units/mL (per mL): $11.18
Suspension Pen-injector (NovoLOG Mix 70/30 FlexPen Subcutaneous)
(70-30) 100 units/mL (per mL): $11.18
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.
SUBQ: Insulin aspart protamine and insulin aspart combination product is administered by SUBQ injection, typically in 2 divided doses/day with each dose intended to cover two meals or a meal and a snack; patients with type 1 diabetes should administer within 15 minutes before meal initiation; patients with type 2 diabetes may administer within 15 minutes before or after meal initiation. 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 and prefilled pens should be gently rolled between the palms ten times; it is important that the vials and pens are kept horizontal throughout this process. After prefilled pens are rolled between the palms, the, prefilled pens should then be inverted until the glass ball moves from one end of the reservoir to the other ten times. Properly resuspended insulin should look uniformly white and cloudy; 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 dilute or mix with any other insulin formulation or solution.
For prefilled pens, prime the needle before each injection with 2 units of insulin. Once injected, hold the needle in the skin for at least 6 seconds after the dose dial has returned to 0 units before removing the needle to ensure the full dose has been administered. NovoLog 70/30 FlexPen is designed to dial doses in 1-unit increments. When there are <12 units remaining in NovoLog 70/30 FlexPen, replace it with a new one to ensure even mixing.
SUBQ: For SUBQ administration into the thigh, upper arm, buttocks, or abdomen; not for IV administration or use in an insulin pump. Rotate 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. Properly resuspended insulin should look uniformly white and cloudy; resuspension is easier at room temperature. 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. Administer within 15 minutes before a meal (type 1 diabetes) or 15 minutes before or after a meal (type 2 diabetes). Do not mix or dilute with other insulins.
Vials: In order to properly resuspend the insulin, gently roll vial horizontally between the palms 10 times.
NovoLog Mix FlexPen: In order to properly resuspend the insulin, the FlexPen should be gently rolled horizontally between the palms 10 times and inverted 180° at least 10 times. Prime the needle before each injection with 2 units of insulin; see manufacturer's labeling for specific procedure. NovoLog 70/30 FlexPen is designed to dial doses in 1-unit increments. Once primed, set dial to the appropriate dose, insert needle into clean skin, and activate device. Once the insulin is injected, hold the needle in the skin for ≥6 seconds after the dose dial has returned to "0," keeping the button pressed the entire time, and then remove the needle. Do not rub the area. When there are <12 units remaining in the FlexPen, replace it with a new one to ensure even mixing.
Diabetes mellitus, types 1 and 2, treatment: Treatment of type 1 diabetes mellitus and type 2 diabetes mellitus to improve glycemic control.
NovoLOG Mix 70/30 may be confused with HumaLOG Mix 75/25, HumuLIN 70/30, NovoLIN 70/30, NovoLOG
NovoLOG Mix 70/30 Flexpen may be confused with NovoLOG Flexpen
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error. Due to the number of insulin preparations, it is essential to identify/clarify the type of insulin to be used.
Cross-contamination may occur if insulin pens are shared among multiple patients. Steps should be taken to prohibit sharing of insulin pens.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alpha-Glucosidase Inhibitors: May enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with an alpha-glucosidase inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification
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. Risk C: Monitor therapy
Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Beta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Beta-Blockers (Nonselective): May enhance the hypoglycemic effect of Insulins. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Insulins. Risk C: Monitor therapy
Bortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Chlorprothixene: May enhance the hypoglycemic effect of Insulins. 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
Etilefrine: May diminish the therapeutic effect of Antidiabetic Agents. 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. Monitor patients for hypoglycemia. Risk D: Consider therapy modification
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Herbal Products with Glucose Lowering Effects: 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: Consider reducing the liraglutide dose if coadministered with insulin. Prescribing information for the Saxenda brand of liraglutide recommends a dose decrease of 50%. Monitor blood glucose for hypoglycemia. 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 for signs and symptoms of hypoglycemia. 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, consider insulin dose reductions to avoid hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure, and consider pioglitazone dose reduction or discontinuation if heart failure occurs 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
Biphasic insulin aspart (insulin aspart protamine suspension 70% [intermediate acting] and insulin aspart solution 30% [rapid acting]) was found to be comparable to biphasic human insulin (Insulin NPH suspension 70% [intermediate acting] and insulin regular solution 30% [short acting]) in initial studies of patients with gestational diabetes mellitus (Balaji 2010; Balaji 2012).
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 malformations, stillbirth, and macrosomia. To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2023; 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 2023).
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 2023).
In a study using insulin aspart, both exogenous and endogenous insulin were present in breast milk (Whitmore 2012). Insulin is not systemically absorbed via breast milk but may provide local benefits to the infant GI tract (Anderson 2018).
Appropriate glycemic control is required for the establishment of lactation in patients with diabetes mellitus (Anderson 2018). Breastfeeding provides metabolic benefits to mothers with type 1, type 2, and gestational diabetes mellitus as well as their infants; therefore, breastfeeding is encouraged (ACOG 201 2018; ADA 2023; Blumer 2013). Breastfeeding also influences maternal glucose tolerance; close monitoring of patients treated with insulin is recommended as dose adjustments may be required (ADA 2023; Anderson 2018). A small snack before breastfeeding may help decrease the risk of hypoglycemia in patients with pregestational diabetes (ACOG 201 2018; Reader 2004). 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.
Most available information for use of insulin aspart in breastfeeding persons is from studies using the rapid action solution. Refer to Insulin Aspart monograph for additional information.
Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.
Diabetes mellitus: Plasma glucose (individualize frequency based on treatment regimen, hypoglycemia risk, and other patient-specific factors) (ADA 2023); electrolytes; 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).
HbA1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met, or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2023; KDIGO 2020).
Recommendations for glycemic control in patients with diabetes:
Nonpregnant adults (AACE [Samson 2023], ADA 2023):
HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note: In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.
Preprandial capillary blood glucose: 80 to 130 mg/dL (SI: 4.4 to 7.2 mmol/L) (more or less stringent goals may be appropriate based on patient-specific characteristics).
Peak postprandial capillary blood glucose (~1 to 2 hours after a meal): <180 mg/dL (SI: <10 mmol/L) (more or less stringent goals may be appropriate based on patient-specific characteristics).
Older adults (≥65 years of age) (ADA 2023):
Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (sulfonylureas, meglitinides) (ES [LeRoith 2019]).
HbA1c: <7% to 7.5% (healthy); <8% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.
Preprandial capillary blood glucose: 80 to 130 mg/dL (SI: 4.4 to 7.2 mmol/L) (healthy); 90 to 150 mg/dL (SI: 5 to 8.3 mmol/L) (complex/intermediate health); 100 to 180 mg/dL (SI: 5.6 to 10 mmol/L) (very complex/poor health).
Bedtime capillary blood glucose: 80 to 180 mg/dL (SI: 4.4 to 10 mmol/L) (healthy); 100 to 180 mg/dL (SI: 5.6 to 10 mmol/L) (complex/intermediate health); 110 to 200 mg/dL (SI: 6.1 to 11.1 mmol/L) (very complex/poor health).
Pregnant patients:
HbA1c: Pregestational diabetes (type 1 or type 2) (ADA 2023):
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: Note: Less stringent targets may be appropriate if goals cannot be achieved without causing significant hypoglycemia (ADA 2023):
Gestational diabetes mellitus (ACOG 190 2018; ADA 2023):
Fasting: <95 mg/dL (SI: <5.3 mmol/L).
Postprandial: <140 mg/dL (SI: <7.8 mmol/L) (at 1 hour) or <120 mg/dL (SI: <6.7 mmol/L) (at 2 hours).
Pregestational diabetes mellitus (type 1 or type 2) (ADA 2023):
Fasting: 70 to 95 mg/dL (SI: 3.9 to 5.3 mmol/L).
Postprandial: 110 to 140 mg/dL (SI: 6.1 to 7.8 mmol/L) (at 1 hour) or 100 to 120 mg/dL (SI: 5.6 to 6.7 mmol/L) (at 2 hours).
Hospitalized adult patients (ADA 2023): Target glucose range: 140 to 180 mg/dL (SI: 7.8 to 10 mmol/L) (majority of critically ill and noncritically ill patients; <140 mg/dL [SI: <7.8 mmol/L] may be appropriate for selected patients, if it can be achieved without excessive hypoglycemia). Initiate insulin therapy for persistent hyperglycemia at ≥180 mg/dL (SI: ≥10 mmol/L).
Perioperative care in adult patients (ADA 2023): Target glucose range during perioperative period: Consider targeting 80 to 180 mg/dL (SI: 4.4 to 10 mmol/L).
Children and adolescents:
Preprandial glucose: 70 to 130 mg/dL (SI: 3.9 to 7.2 mmol/L) (ISPAD [Dimeglio 2018]).
Postprandial glucose: 90 to 180 mg/dL (SI: 5 to 10 mmol/L) (ISPAD [Dimeglio 2018]).
Bedtime/overnight glucose: 80 to 140 mg/dL (SI: 4.4 to 7.8 mmol/L) (ISPAD [Dimeglio 2018]).
HbA1c: <7%; target should be individualized; a more stringent goal (<6.5%) may be reasonable if it can be achieved without significant hypoglycemia; less aggressive goals (<7.5% or <8%) may be appropriate in patients who cannot articulate symptoms of hypoglycemia, cannot check glucose frequently, have a history of severe hypoglycemia, or have extensive comorbid conditions (ADA 2023; ISPAD [Dimeglio 2018]).
Surgical patients (ISPAD [Jefferies 2018]):
Intraoperative: 90 to 180 mg/dL (SI: 5 to 10 mmol/L).
ICU, postsurgery: 140 to 180 mg/dL (SI: 7.8 to 10 mmol/L).
Classification of hypoglycemia (ADA 2023):
Level 1: 54 to 70 mg/dL (SI: 3 to 3.9 mmol/L); hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.
Level 2: <54 mg/dL (SI: <3 mmol/L); 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.
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. Insulin stimulates lipoprotein lipase synthesis and activity; this results in hydrolysis of triglycerides into free fatty acids and storage of free fatty acids in adipocytes, thereby reducing circulating triglyceride levels (Rawla 2018; Sadur 1982; Song 2019). 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. Insulin aspart differs from human insulin by containing aspartic acid at position B28 in comparison to the proline found in human insulin. Insulins are categorized based on the onset, peak, and duration of effect (eg, rapid-, short-, intermediate-, and long-acting insulin). Insulin aspart protamine and insulin aspart combination consists of an intermediate-acting insulin (aspart protamine) and a rapid-acting insulin (aspart).
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: 10 to 20 minutes.
Peak effect: 1 to 4 hours.
Duration: NovoLog Mix 70/30: 18 to 24 hours.
Protein binding: ≤9%.
Half-life elimination: NovoLog Mix 70/30: ~8 to 9 hours.
Time to peak, plasma: 1 to 1.5 hours.
Altered kidney function: Insulin Cl may be reduced in patients with impaired renal function.
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