Exogenous Insulin Products
Exogenous Insulin Products - Index
Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Texas Vendor Drug Program formulary coverage.
- Revision history
- Oct. 13, 2023
- Oct. 22, 2021
- Sept. 2019.
- Initially developed
- June 2017
1. Dosage
1.1. Background
Insulin is a hormone that is typically produced and secreted from pancreatic beta cells in response to elevated blood glucose by binding to receptors found on the liver, skeletal muscle, and adipose tissue cells. Carbohydrate, protein, and fat metabolism are regulated by insulin through suppressing hepatic glucose production, stimulating tissue glucose uptake, and suppressing free fatty acid release from adipose tissue. Subsequently, blood glucose levels are reduced through insulin’s mechanism. 1-3
However, there is inadequate or no insulin secretion in type 1 diabetes mellitus (DM), and there is insulin deficiency and resistance in type 2 DM. Therefore, patients with type 1 DM require insulin treatment to survive; patients with type 2 DM may require insulin when other antidiabetic agents are not able to effectively control blood glucose levels. If either type 1 or 2 DM are left untreated and/or uncontrolled, chronic hyperglycemia may lead to micro- and macrovascular complications, such as retinopathy, nephropathy, neuropathy, hypertension, dyslipidemia, and cardiovascular disease. 1-7
Exogenous insulin products are FDA-approved for use in type 1 and 2 DM. These products are used to mimic the physiologic pattern of insulin secretion. Phase 1 is basal insulin secretion, which suppresses hepatic glucose production in order to maintain blood glucose levels throughout the day. Phase 2 is increased insulin secretion in response to carbohydrate intake in order to lower postprandial blood glucose levels. Patients with type 1 DM require both basal and preprandial insulin boluses, while patients with type 2 DM may require basal and/or preprandial insulin boluses in addition to oral antidiabetic agents, diet, exercise, and weight reduction depending on the severity of their disease and glycemic control. 1-7
Glycemic targets recommended by the American Diabetes Association (ADA) and American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) guidelines are summarized in Table 1 2, 8, 9. However, these targets should be individualized based on patient factors, such as life expectancy, severity of disease, comorbidities, and hypoglycemic risk. 2,8,9
Glycemic Targets | ADA – Type 1 and 2 | AACE/ACE – Adult Type 2 |
---|---|---|
Hemoglobin A1c | Adults & Pediatrics: less than 7%
| Greater than or less than 6.5% |
Preprandial blood glucose | Adults: 80–130 mg/dL
| Less than 110 mg/dL |
Postprandial blood glucose | Adults: less than 180 mg/dL | Less than 140 mg/dL |
Bedtime blood glucose | Adults & Pediatrics: 90–150 mg/dL*
| N/A |
Legend:
- ! Less stringent A1c goals of less than 7.5% may be appropriate in pediatric and adolescent patients who cannot articulate hypoglycemia symptoms; have hypoglycemia unawareness; lack access to analog insulins, advanced insulin delivery technology, and/or continuous glucose monitoring; cannot check blood glucose regularly, or have nonglycemic factors that increase A1c. A goal of less than 8.0% may be appropriate in pediatric an adolescent patients with a history of severe hypoglycemia, limited life expectancy, or where harms of treatment outweigh the benefits
- * Recommendations carried over from 2019 ADA Standards of Medical Care in Diabetes since they are not presented in the 2021 guidelines.
1.2. Adults
Dosage forms, usual dosage regimen, and maximum recommended dosage of exogenous insulin products for adult patients, categorized by time of onset, peak, and duration of action, are summarized in Tables 2-7. Lyumjev and Lyumjev KwikPen (insulin lispro) is a rapid-acting insulin that was approved in June 2020 for subcutaneous use as an injection or with an insulin pump. It is also approved for intravenous use.19 Semglee (insulin glargine-yfgn) was approved by the FDA in July 2021, and it is the first FDA approved interchangeable biosimilar insulin product. Semglee is interchangeable with Lantus (insulin glargine).
Drug Name | Dosage Form | Labeled Dosage Regimen for Type 1 Diabetes * | Labeled Dosage Regimen for Type 2 Diabetes * |
---|---|---|---|
Insulin aspart |
|
|
|
Insulin glulisine |
|
|
|
Insulin lispro |
|
|
|
Legend:
- Multiple or continuous insulin dosing may be required to maintain adequate glycemic control; should be individualized for each patient
- No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
- Total daily doses of ALL insulin formulations combined is typically: 0.5 to 1 units/kg/day
- Insulin needs may be affected by body weight; non-obese patients may require less insulin than obese patients
- Non-obese: 0.4 to 0.6 units/kg/day
- Obese: 0.8 to 1.2 units/kg/day
Drug Name | Dosage Form | Labeled Dosage Regimen for Type 1 Diabetes * | Labeled Dosage Regimen for Type 2 Diabetes * |
---|---|---|---|
Inhaled insulin |
|
|
|
Regular insulin |
|
|
|
Legend:
- Multiple or continuous insulin dosing may be required to maintain adequate glycemic control; should be individualized for each patient
- No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
- Total daily doses of ALL insulin formulations combined is typically: 0.5 to 1 units/kg/day
- Insulin needs may be affected by body weight; non-obese patients may require less insulin than obese patients
- Non-obese: 0.4 to 0.6 units/kg/day
- Obese: 0.8 to 1.2 units/kg/day
Drug Name | Dosage Form | Labeled Dosage Regimen for Type 1 Diabetes * | Labeled Dosage Regimen for Type 2 Diabetes * |
---|---|---|---|
Isophane insulin (NPH) |
|
|
|
Legend:
- Multiple or continuous insulin dosing may be required to maintain adequate glycemic control; should be individualized for each patient
- No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
- Total daily doses of ALL insulin formulations combined is typically: 0.5 to 1 units/kg/day
- Insulin needs may be affected by body weight; non-obese patients may require less insulin than obese patients
- Non-obese: 0.4 to 0.6 units/kg/day
- Obese: 0.8 to 1.2 units/kg/day
Drug Name | Dosage Form | Labeled Dosage Regimen for Type 1 Diabetes * | Labeled Dosage Regimen for Type 2 Diabetes * |
---|---|---|---|
Insulin degludec | Tresiba generic vial (100 units/mL – 10 mL) Tresiba generic FlexTouch pen (100 units/mL – 5 x 3 mL; 200 units/mL – 3 x 3 mL) | Initially, administer 1/3 to 1/2 of total daily insulin dose once daily Administer remainder as short-acting insulin & divided between each daily meal Insulin naive patients generally require total daily insulin dose of 0.2 - 0.4 units/kg/day Insulin degludec may be given any time of day; however, doses must be at least 8 hours apart | In adults naive to insulin, initiate with 10 units once daily Insulin degludec may be given at any time of day; however, doses must be at least 8 hours apart Titrate dosage every 3-4 days to achieve blood glucose & a1c goals in conjunction with short-acting insulin |
Insulin detemir |
|
|
|
Insulin glargine |
|
|
|
Legend:
- Multiple or continuous insulin dosing may be required to maintain adequate glycemic control; should be individualized for each patient
- No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
- Total daily doses of ALL insulin formulations combined is typically: 0.5 to 1 units/kg/day
- Insulin needs may be affected by body weight; non-obese patients may require less insulin than obese patients
- Non-obese: 0.4 to 0.6 units/kg/day
- Obese: 0.8 to 1.2 units/kg/day
Drug Name | Dosage Form | Usual Dosage Regimen * | Maximum Recommended Dosage * |
---|---|---|---|
Insulin aspart protamine/insulin aspart |
|
|
|
Isophane insulin (NPH)/ regular insulin |
|
|
|
Insulin lispro protamine/insulin lispro |
|
|
|
Legend:
- Multiple or continuous insulin dosing may be required to maintain adequate glycemic control; should be individualized for each patient
- No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
- Total daily doses of ALL insulin formulations combined is typically: 0.5 to 1 units/kg/day
- Insulin needs may be affected by body weight; non-obese patients may require less insulin than obese patients
- Non-obese: 0.4 to 0.6 units/kg/day
- Obese: 0.8 to 1.2 units/kg/day
Drug Name | Dosage Form | Usual Dosage Regimen | Maximum Recommended Dosage |
---|---|---|---|
Insulin glargine/lixisenatide | Soliqua® 100/33 pen (insulin glargine 100 units/mL and lixisenatide 33 mcg/mL – 5 x 3 mL) | 15 – 60 units/day | (15 – 60 units / 5 – 20 mcg) 60 units/20 mcg/day |
Insulin degludec/liraglutide | Xultophy® 100/3.6 pen (insulin degludec 100 units/mL and liraglutide 3.6 mg/mL – 5 x 3 mL) | 10 – 50 units/day (10 – 50 units / 0.36 – 1.8 mg) | 50 units/1.8 mg/day |
Legend:
- GLP-1 = glucagon-like peptide-1
1.3. Pediatrics
Safety and efficacy for inhaled insulin (Afrezza), insulin lispro/lispro protamine combinations (HumaLog Mix 50/50 and 75/25), insulin aspart/insulin aspart protamine combinations (NovoLog Mix 70/30), and insulin-GLP-1 combinations (Soliqua 100/33 and Xultophy 100/3.6) have not been studied or established in pediatric patients. 10-13, 14, 19, 32, 35, 36-38
The insulin aspart formulation sold under the trade name Fiasp was approved for pediatric use in patients 2 years of age or older in 2020.39
Recommended age requirements for insulin products approved in pediatric patients are summarized in the following tables.
Usual dosage regimens and maximum recommended dosages are similar to adult patients.
Drug Name | Dosage Form | Approved Age Requirements * | Maximum Recommended Dosage * |
---|---|---|---|
Insulin aspart |
| Children greater than or equal to 2 years and adolescents | No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs |
Insulin glulisine |
| Children greater than or equal to 4 years and adolescents | No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs |
Insulin lispro |
| Children greater than or equal to 3 years and adolescents | No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs |
Legend:
- No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
Drug Name | Dosage Form | Approved Age Requirements * | Maximum Recommended Dosage * |
---|---|---|---|
Regular insulin |
| No specific age requirement reported | No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs |
Legend:
- No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
Drug Name | Dosage Form | Approved Age Requirements * | Maximum Recommended Dosage * |
---|---|---|---|
Isophane insulin (NPH) |
| No specific age requirement reported | No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs |
Legend:
- No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
Drug Name | Dosage Form | Approved Age Requirements * | Maximum Recommended Dosage * |
---|---|---|---|
Insulin degludec |
|
| No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs |
Insulin detemir |
| Children greater than 2 years and adolescents | No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs |
Insulin glargine |
| Children greater than 6 years and adolescents | No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs |
Legend:
- No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
Drug Name | Dosage Form | Approved Age Requirements * | Maximum Recommended Dosage * |
---|---|---|---|
Isophane insulin (NPH) and regular insulin |
| Children and adolescents | No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs |
Legend:
- No maximum recommended dosage to exceed; insulin and other antidiabetic drugs should be adjusted to target glycemic goals and meet patients’ needs
2. Duration of Therapy
Exogenous insulin products are indicated for the management of type 1 and 2 DM and may be continued indefinitely, as blood glucose control in DM is a chronic, lifelong process. 1-9
3. Duplicative Therapy
Adjunctive administration of multiple exogenous insulin products may be required or recommended to maintain adequate glycemic control. If multiple exogenous insulin products are required or recommended, the patients generally have one long-acting or intermediate-acting basal insulin product and one short- or rapid-acting preprandial insulin product 1-38. Patient profiles containing prescriptions for multiple short-acting or multiple long-acting exogenous insulin products will be reviewed.
4. Drug-Drug Interactions
Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for exogenous insulin products are summarized in Table 13. Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.
Target Drug: all insulin products
Interacting Drug | Interaction | Recommendation | Clinical Significance Level |
---|---|---|---|
angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) | adjunctive use may increase hypoglycemia risk as ACE inhibitors, ARBS improve insulin sensitivity | monitor blood glucose levels and observe for signs/symptoms of hypoglycemia | moderate (CP) |
beta blockers | combined use may increase or decrease blood glucose levels as beta blockers can alter glucose metabolism; beta blockade may also mask hypoglycemia signs/symptoms | monitor patients for signs/ symptoms of hypo- or hyperglycemia with combined therapy; measure blood glucose levels | moderate (CP) |
glucagon-like peptide-1 (GLP-1) receptor agonists | concurrent use may increase hypoglycemia risk | monitor blood glucose levels and consider insulin dose reductions or therapy modification; avoid combination of liraglutide and insulin if liraglutide is used primarily for weight loss | major (CP) |
lithium | combined use may increase risk of hypo- or hyperglycemia due to lithium varying effects on glucose metabolism | monitor blood glucose levels, especially when adding, discontinuing, modifying therapy | moderate (CP) |
metreleptin (Myalept®) | concurrent use may increase risk of hypoglycemia | use with caution and monitor blood glucose levels closely; potential large decreases in insulin dosage adjustments may be required, or consider therapy modification | moderate (CP) |
peroxisome proliferator-activated receptor (PPAR)-gamma agonists | insulin may enhance rosiglitazone, pioglitazone adverse effects (e.g., edema, heart failure); combined use may increase hypoglycemia risk | avoid combination with rosiglitazone; if insulin is combined with pioglitazone, consider dose reductions or therapy modification; monitor patients for signs/symptoms of heart failure and hypoglycemia | major (CP) |
pramlintide | concurrent use may increase hypoglycemia risk | decrease preprandial insulin dose by 50% or consider therapy modification; monitor blood glucose frequently and adjust insulin dose based on glycemic control | major (CP) |
fluoroquinolone antibiotics | concomitant use may increase risk of hypo- or hyperglycemia | monitor blood glucose levels closely and adjust insulin dose as needed; further insulin dosage adjustments may be required upon fluoroquinolone discontinuation | moderate (CP) |
somatostatin analogs | concurrent use may diminish insulin therapeutic effects as somatostatin analogs associated with hyperglycemia | monitor blood glucose levels frequently and adjust insulin dose as needed | moderate (CP) |
5. References
- Trujillo J, Yee GC, Haines S. Diabetes Mellitus. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. DiPiro J.T., & Yee G.C., & Posey L, & Haines S.T., & Nolin T.D., & Ellingrod V(Eds.),Eds. Joseph T. DiPiro, et al.eds. Pharmacotherapy: A Pathophysiologic Approach, 12e. McGraw Hill; 2023. Accessed August 28th, 2023. https://accesspharmacy-mhmedical-com.ezproxy.lib.utexas.edu/content.aspx?bookid=3097§ionid=269398080
- Samson SL, Vellanki P, Blonde L, et. al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm- 2023 update. Endocr Pract. 2023 May;29(5):305-340.
- American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2023;46 (Suppl 1):S140-157.
- Weinstock RS. General principles of insulin therapy in diabetes mellitus. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed August 28th, 2023.)
- Weinstock RS. Management of blood glucose in adults with type 1 diabetes mellitus. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed August 28th, 2023.)
- Levitsky LL, Misra M. Insulin therapy for children and adolescents with type 1 diabetes mellitus. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed August 28th, 2023.)
- Wexler JW. Insulin therapy in type 2 diabetes mellitus. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed August 28th, 2023.)
- American Diabetes Association. 6. Glycemic targets: Standards of medical care in diabetes – 2023. Diabetes Care. 2023;46 (Suppl 1): s97-s110.
- American Diabetes Association. 13. Older adults: Standards of medical care in diabetes – 2023. Diabetes Care. 2023;46 (Suppl 1): s216-s229.
- American Diabetes Association. 14. Children and adolescents: Standards of medical care in diabetes – 2023. Diabetes Care. 2023;46 (Suppl 1)S230-S253.
- IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: September 6, 2023).
- Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed September 6, 2023.
- Insulin aspart (Fiasp®) package insert. NovoNordisk, June 2023.
- Insulin aspart (NovoLog®) package insert. Novo Nordisk, February 2023.
- Insulin glulisine (Apidra®) package insert. Sanofi-Aventis, July 2023.
- Insulin lispro (Admelog®) package insert. Sanofi-Aventis, November 2020.
- Insulin lispro (Humalog®) package insert. Eli Lilly, August 2023.
- Insulin lispro (Lyumjev®) package insert. Eli Lilly and Company, March 2023.
- Regular insulin (Afrezza®) package insert. MannKind Corporation, February 2023.
- Regular insulin (Humulin® R) package insert. Eli Lilly, January 2023.
- Regular insulin (Humulin® R Concentrated U 500) package insert. Eli Lilly,
June 2022. - Regular insulin (Novolin® R) package insert. Novo Nordisk, November 2022.
- Insulin isophane (NPH) (Humulin® N) package insert. Eli Lilly, March 2023.
- Insulin isophane (NPH) (Novolin® N) package insert. Novo Nordisk, November 2022.
- Insulin degludec (Tresiba®) package insert. Novo Nordisk, July 2022.
- Insulin detemir (Levemir®) package insert. Novo Nordisk, December 2022.
- Insulin glargine (Basaglar®, KwikPen™, Tempo Pen™) package insert. Eli Lilly, June 2023.
- Insulin glargine (Lantus®, Solostar™) package insert. Sanofi-Aventis, June 2023.
- Insulin glargine-aglr (Rezvoglar®, Kwikpen™) package insert. Eli Lilly and Company, November 2022.
- Insulin glargine-yfgn (Semglee®) package insert. Mylan Specialty LP, July 2023.
- Insulin glargine (Toujeo®, Toujeo Max®) package insert. Sanofi-Aventis, March 2023.
- Insulin aspart protamine and insulin aspart (NovoLog® Mix 70/30) package insert. Novo Nordisk, February 2023.
- Insulin isophane (NPH) and regular (Humulin® 70/30) package insert. Eli Lilly, March 2023.
- Insulin isophane (NPH) and regular (Novolin® 70/30) package insert. Novo Nordisk, November 2022.
- Insulin lispro (Humalog® Mix 50/50) package insert. Eli Lilly, July 2023.
- Insulin lispro (Humalog® Mix 75/25) package insert. Eli Lilly, July 2023.
- Insulin glargine and lixisenatide (Soliqua® 100/33) package insert. Sanofi-Aventis, June 2022.
- Insulin degludec and liraglutide (Xultophy® 100/3.6) package insert. Novo Nordisk, July 2023.
- Melillo G. FDA approves Fiasp for children with diabetes. Am J Manag Care. January 6, 2020. Available at: www.ajmc.com/view/fda-approves-fiasp-for-children-with-diabetes. Accessed September 6, 2023.