Insulin Glargine

Dosage Forms

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

Solution, Subcutaneous:

Lantus: 100 units/mL (10 mL) [contains metacresol]

Solution Pen-injector, Subcutaneous:

Basaglar KwikPen: 100 units/mL (3 mL) [contains metacresol]

Lantus SoloStar: 100 units/mL (3 mL) [contains metacresol]

Toujeo Max SoloStar: 300 units/mL (3 mL) [contains metacresol]

Toujeo SoloStar: 300 units/mL (1.5 mL) [contains metacresol]

Pharmacology

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. Insulin glargine differs from human insulin by adding two arginines to the C-terminus of the B-chain in addition to containing glycine at position A21 in comparison to the asparagine 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 glargine is a long-acting insulin analog.

Pharmacokinetics/Pharmacodynamics

Absorption

Slow; upon injection into the subcutaneous tissue, microprecipitates form which allow small amounts of insulin glargine to release over time

Metabolism

Partially metabolized in the subcutaneous depot at the carboxyl terminus of the B chain to form two active metabolites, M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin)

Excretion

Urine

Onset of Action

Basaglar: Peak effect: No pronounced peak

Lantus: 3 to 4 hours; Peak effect: No pronounced peak

Toujeo: 6 hours; Peak effect: Maximum glucose lowering effect may take up to 5 days with repeat dosing; at steady state, the 24-hour glucose lowering effect is ~27% lower than that of Lantus at equivalent doses.

Time to Peak

Plasma: Lantus: No pronounced peak; Basaglar: ~12 hours; Toujeo: median of 12 to 16 hours (dose dependent)

Duration of Action

Lantus, Basaglar: Generally 24 hours or longer; reported range (Lantus): 10.8 to >24 hours (up to ~30 hours documented in some studies) (Heinemann 2000); Toujeo: >24 hours

Use in Specific Populations

Special Populations: Renal Function Impairment

Insulin Cl may be reduced in patients with impaired renal function.

Use: Labeled Indications

Diabetes mellitus, types 1 and 2: To improve glycemic control in adults with type 1 diabetes mellitus and type 2 diabetes mellitus; to improve glycemic control in children ≥6 years of age with type 1 diabetes mellitus (Lantus and Basaglar only)

Contraindications

Hypersensitivity to insulin glargine or any component of the formulation; during episodes of hypoglycemia

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

Dosage and Administration

Dosing: Adult

Note: Insulin glargine is a long-acting insulin. Insulin requirements vary dramatically between patients and dictates frequent monitoring and close medical supervision.

Diabetes mellitus, type 1: SubQ:

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

General insulin dosing:

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

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

Division of TDD (multiple daily injections):

Basal insulin: Generally, 40% to 50% of the TDD is given as basal insulin (intermediate- or long-acting) (AACE/ACE [Handelsman 2015]; ADA 2019). Insulin glargine may be administered as a single daily dose (manufacturer's labeling); in some cases, administration of insulin glargine (Lantus formulation) as 2 divided doses may be beneficial (Ashwell 2006; Youssef 2010).

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

Dosage adjustment: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Adjust dose to maintain premeal and bedtime glucose in target range. Since combinations of agents are frequently used, dosage adjustment must address the individual component of the insulin regimen that most directly influences the blood glucose value in question, based on the known onset and duration of the insulin component. To minimize hypoglycemia risk, basal insulins are generally titrated once or twice weekly (eg, every 3 or 7 days) (ADA 2019; McCall 2012).

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

Initial:10 units or 0.1 to 0.2 units/kg once daily (ADA 2019). If HbA_1c >8% prior to initiation of basal insulin, 0.2 to 0.3 units/kg once daily is recommended (AACE/ACE [Garber 2019]).

Dosage adjustment:

To reach fasting plasma glucose (FPG) target: Adjust dose using evidence-based titration algorithm (eg, by 2 units every 3 days) while avoiding hypoglycemia (AACE/ACE [Garber 2019]; ADA 2019).

Note: Although typically administered once daily, administration of insulin glargine (U-100/Lantus formulation) as 2 divided doses has also been reported; evidence and guidance related to this practice is limited, but twice-daily dosing may occasionally be an option in patients requiring higher doses or with practical barriers to optimizing a once-daily insulin glargine dose (eg, morning hypoglycemia following evening administration, premature loss of glycemic control towards the end of the dosing interval) (Barnett 2006; Eledrisi 2018; Housel 2010).

If HbA_1c remains above target despite achieving FPG target, or if insulin glargine dose is >0.4 to 0.5 units/kg/day, consider intensification of therapy with additional agents that target postprandial glucose rather than continuing to increase the insulin glargine dose; higher insulin glargine doses may provide only diminishing improvements in FPG and/or HbA_1c (AACE/ACE [Garber 2019]; ADA 2019; Umpierrez 2019).

For hypoglycemia: If no clear reason for hypoglycemia, decrease dose by 10% to 20% (ADA 2019); for severe hypoglycemia (ie, requiring assistance from another person or blood glucose <40 mg/dL), reduce dose by 20% to 40% (AACE/ACE [Garber 2019]).

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

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

Basal component: SubQ: Continue previous basal insulin dose or administer 30% to 50% of current TDD as insulin glargine; if basal insulin naive, administer insulin glargine 10 units once daily.

Patients with diabetes undergoing surgery (ADA 2019): SubQ: On the morning of surgery or procedure, give 60% to 80% of the usual dose of long-acting analogs (eg, glargine, degludec, detemir).

Conversion to insulin glargine from other insulin therapies:

Converting from once-daily NPH insulin to insulin glargine: May be substituted on an equivalent unit-per-unit basis.

Converting from twice-daily NPH insulin to insulin glargine: Initial dose: Use 80% of the total daily dose of NPH (eg, 20% reduction); administer once daily; adjust dosage according to patient response.

Conversion between Toujeo, Lantus, or Basaglar:

Conversion from once-daily Toujeo to once-daily Lantus or once-daily Basaglar: Initial dose: Use 80% of the dose of Toujeo (eg, 20% reduction); adjust dosage according to patient blood glucose response.

Conversion from once-daily Lantus to once-daily Toujeo or once-daily Basaglar: Initial dose: May be substituted on an equivalent unit-per-unit basis; however, generally a higher daily dosage of Toujeo will be required to achieve the same level of glycemic control as with Lantus.

Conversion between Toujeo SoloStar and Toujeo Max SoloStar (or Toujeo DoubleStar [Canadian product]): If previous dose was an odd number, the dose should be increased or decreased by 1 unit.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Insulin glargine is a long-acting insulin. Insulin glargine is approximately equipotent to human insulin, but has a slower onset, no pronounced peak, and a longer duration of activity. Insulin doses should be individualized based on patient needs; adjustments may be necessary with changes in physical activity, meal patterns, acute illness, or with changes in renal or hepatic function. Insulin requirements vary dramatically between patients and dictates frequent monitoring and close medical supervision. Insulin regimens vary widely by region, practice, and institution; consult institution-specific guidelines.

Type 1 diabetes mellitus: Children and Adolescents: Note: For basal insulin coverage, long-acting insulin analogs are preferred over insulin NPH due to decreased risk of hypoglycemia (AACE/ACE [Handelsman 2015]; ADA 2019; ADA [Chiang 2014]). Insulin glargine must be used in combination with a rapid or short-acting insulin. The daily doses presented are expressed as the total units/kg/day of all insulin formulations used.

Insulin glargine-specific dosing: Note: All pediatric patients should have rapid-acting or regular insulin available for crisis management (ISPAD [Danne 2018]).

Initial dose: Children ≥6 years and Adolescents:

Lantus, Basaglar: SubQ: Approximately one-third of the total daily insulin requirement administered once daily; a rapid-acting or short-acting insulin should also be used to complete the balance (~²/₃) of the total daily insulin requirement. Adjust dosage according to patient response.

Toujeo: SubQ: Approximately one-third to one-half of the total daily insulin requirement administered once daily; a rapid-acting or short-acting insulin should also be used to complete the balance of the total daily insulin requirement. Adjust dosage according to patient response.

General insulin dosing:

Initial total daily insulin: SubQ: Initial: 0.4 to 0.5 units/kg/day in divided doses (AACE/ACE [Handelsman 2015]; ADA 2019); Usual range: 0.4 to 1 units/kg/day in divided doses (AACE/ACE [Handelsman 2015]; ADA 2019; 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 2019).

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

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

Prepubertal children (not in partial remission):

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

Children ≥7 years: 0.7 to 1 units/kg/day.

Pubescent Children and Adolescents: During puberty, requirements may substantially increase to >1 unit/kg/day and in some cases up to 2 units/kg/day.

Division of daily insulin requirement (multiple daily injections):

Basal insulin: Generally, ~30% to 50% of the total daily insulin is given as basal insulin (intermediate- or long-acting) in 1 to 2 daily injections (AACE/ACE [Handelsman 2015]; ADA 2019; ISPAD [Danne 2018]; Peters 2013).

Prandial insulin: The remaining portion of the total daily dose is then divided and administered before or at mealtimes (depending on the formulation) as a rapid-acting (eg, aspart, glulisine, lispro) or short-acting (regular). In most type 1 patients, the use of a rapid-acting insulin analog is preferred over regular insulin to reduce hypoglycemia risk (AACE/ACE [Handelsman 2015]; ADA 2019; ADA [Chiang 2014]; ISPAD [Danne 2018]).

Dosage 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.

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

Minor surgeries:

Morning procedure: Administer the usual insulin glargine dose (if usually given in the morning); may consider reducing dose to 70% to 80% of usual dose if preoperative evaluation shows low morning blood glucose values. Alternatively, may administer IV insulin (regular) infusion; begin IV fluids containing dextrose; in general rapid acting insulin should be omitted until after surgery and patient is able to eat unless it is needed to correct significant hyperglycemia and/or significant ketone (>0.1 mmol/mol) production is present.

Afternoon procedure: Administer the usual morning dose of insulin glargine (if usually given in the morning).

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

Major surgeries:

Evening prior to surgery: If patient normally receives evening insulin doses, administer 50% to 100% of the usual evening and/or bedtime insulin glargine; patients on continuous subcutaneous insulin infusion (CSII) may continue normal insulin basal rates overnight; if there is a concern for hypoglycemia, basal rate may be reduced by 20% at ~3 am.

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

Type 2 diabetes mellitus: Limited data available: Note: The goal of therapy is to achieve an HbA_1c <7% as quickly as possible using the safe titration of medications.

Toujeo-specific dosing: Children ≥6 years and Adolescents: SubQ: Initial: 0.2 units/kg/dose once daily.

General insulin dosing:

Newly diagnosed patients: Note: Recommended for use in metabolically unstable patients (eg, plasma glucose ≥250 mg/dL, HbA_1c >8.5%, and symptoms excluding acidosis) while metformin is initiated and titrated (ADA [Arslanian 2018]; ADA 2019); may also be used for patients with ketosis/ketoacidosis/ketonuria to correct the hyperglycemia and the metabolic derangement (ADA [Arslanian 2018]; ISPAD [Zeitler 2018]).

Children ≥10 years and Adolescents: SubQ:

Initial therapy: 0.25 to 0.5 units/kg/dose once daily; titrate every 2 to 3 days as needed based on plasma glucose; use in combination with lifestyle changes and metformin to achieve goals.

Subsequent therapy:

Glycemic goal achieved: 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 2019; ADA [Arslanian 2018]; ISPAD [Zeitler 2018]).

Failure to achieve glycemic goal: In patients who fail to achieve glycemic goals with insulin glargine (up to 1.5 units/kg/day) and maximum metformin dose, may consider dividing insulin glargine dose into multiple daily injections (eg, twice daily) and/or initiating prandial insulin (regular insulin or rapid-acting insulin) (ADA [Arslanian 2018]; ISPAD [Zeitler 2018]). Note: Insulin resistance is common with type 2 diabetes and doses >1.5 units/kg/day may be necessary to achieve glycemic control especially in patients with high A_1c and patients in mid to late puberty; may consider use of more concentrated insulin glargine preparations (U-300 [Toujeo]) to avoid large volume injections that may affect medication adherence (ADA [Arslanian 2018]).

Patients on established therapy: Note: Recommended for use when glycemic goals can no longer be met using metformin alone, or if contraindications or intolerable side effects of metformin develop (ADA [Arslanian 2018]).

Children ≥10 years and Adolescents: SubQ: Initial: 0.25 to 0.5 units/kg/dose once daily; may be used alone or in combination with metformin (if not contraindicated); may be titrated as needed based on plasma glucose. If glycemic goals are not achieved at 1.5 units/kg/day evaluate adherence; if adherence confirmed, may consider dividing insulin glargine dose into multiple daily injections (eg, twice daily) and/or initiating prandial insulin (regular insulin or rapid-acting insulin) (ADA [Arslanian 2018]; ISPAD [Zeitler 2018]). Note: Insulin resistance is common with type 2 diabetes and doses >1.5 units/kg/day may be necessary to achieve glycemic control especially in patients with high A_1c and patients in mid to late puberty; may consider use of more concentrated insulin glargine preparations (U-300 [Toujeo]) to avoid large volume injections that may affect medication adherence (ADA [Arslanian 2018]).

Conversion to insulin glargine from NPH insulin: Children ≥2 years and Adolescents: SubQ: Note: Limited data available in children <6 years of age (Colino 2005).

Converting from once-daily NPH insulin to insulin glargine: May be substituted on an equivalent unit-per-unit basis.

Converting from twice-daily NPH insulin to insulin glargine: Initial dose: Use 80% of the total daily dose of NPH (eg, 20% reduction); administer once daily; adjust dosage according to patient response.

Conversion between Toujeo, Lantus, or Basaglar: Children ≥6 years and Adolescents: SubQ:

Conversion from once-daily Toujeo to once-daily Lantus or once-daily Basaglar: Initial dose: Use 80% of the dose of Toujeo (eg, 20% reduction); adjust dosage according to patient blood glucose response.

Conversion from once-daily Lantus to once-daily Toujeo or once-daily Basaglar: Initial dose: May be substituted on an equivalent unit-per-unit basis; however, generally a higher daily dosage of Toujeo will be required to achieve the same level of glycemic control as with Lantus.

Conversion between Toujeo SoloStar and Toujeo Max SoloStar: Children ≥6 years and Adolescents: SubQ: If previous dose was an odd number, the dose should be increased or decreased by 1 unit to accommodate the 2 unit dosing increment on the Max SoloStar device.

Administration

SubQ: Do not use if solution is viscous or cloudy; use only if clear and colorless with no visible particles. Insulin glargine should be administered consistently at the same time each day. Cold injections should be avoided. SubQ administration is usually made into the thighs, arms, buttocks, or abdomen; absorption rates vary amongst injection sites; be consistent with area used while rotating injection sites within the same region to avoid 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. Do not dilute or mix insulin glargine with any other insulin formulation or solution. Insulin glargine prefilled pens are available in concentrations of 100 units/mL and 300 units/mL. Prefilled pens are calibrated to display the actual insulin units administered (no dosage conversion needed) and will administer up to 80 units per injection, in 1 unit increments (Lantus SoloStar, Basaglar KwikPen, Basaglar Tempo Pen, Toujeo SoloStar) or up to 160 units per injection, in 2 unit increments (Toujeo Max SoloStar, Toujeo DoubleStar [Canadian product]). Toujeo Max SoloStar and Toujeo DoubleStar (Canadian product) prefilled pens are only recommended for use in patients requiring at least 20 units of insulin glargine per day. Do not use a syringe to withdraw concentrated insulin glargine (300 units/mL) from a prefilled pen for administration. Cartridges (Canadian product) are to be used only with reusable pens recommended by the manufacturer (refer to product labeling).

Dietary Considerations

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

Storage

Basaglar:

Prefilled pens: Store unopened prefilled pens at room temperature <30°C (<86°F) for 28 days, or refrigerated at 2°C to 8°C (36°F to 46°F) until expiration date. Once in use, store prefilled pens at room temperature <30°C (<86°F) and use within 28 days; do not refrigerate. Do not freeze or use if previously frozen; protect from heat and light.

Cartridges [Canadian product]: Store unopened cartridges refrigerated at 2°C to 8°C (36°F to 46°F) until expiration date. Once in use, store cartridges at room temperature <30°C (<86°F) and use within 28 days; do not refrigerate. Do not freeze or use if previously frozen; protect from heat and light.

Lantus: Store unopened vials and prefilled pens refrigerated at 2°C to 8°C (36°F to 46°F) until expiration date, or at room temperature <30°C (<86°F) for 28 days; do not freeze; protect from heat and sunlight. Once punctured (in use), store vials refrigerated or at room temperature <30°C (<86°F) and use within 28 days. Store prefilled pens (SoloStar) that have been punctured (in use) at temperatures <30°C (<86°F) and use within 28 days; do not freeze or refrigerate.

Toujeo: Store unopened prefilled pen (SoloStar, Max SoloStar, or DoubleStar [Canadian product]) at 2°C to 8°C (36°F to 46°F) until expiration date; do not freeze (discard pen if it has been frozen). Store prefilled pens that have been opened (in use) at <30°C (<86°F) and use within 56 days (SoloStar or Max SoloStar) or 42 days (DoubleStar [Canadian product]); do not freeze or refrigerate. Protect from heat and light.

Drug Interactions

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

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

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

Beta-Blockers: May enhance the hypoglycemic effect of Insulins. Exceptions: Levobunolol; Metipranolol. Monitor therapy

Dipeptidyl Peptidase-IV Inhibitors: May enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification

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

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

Glucagon-Like Peptide-1 Agonists: May enhance the hypoglycemic effect of Insulins. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Exceptions: Liraglutide. Consider therapy modification

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

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

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

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

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Liraglutide: May enhance the hypoglycemic effect of Insulins. Management: If liraglutide is used for the treatment of diabetes (Victoza), consider insulin dose reductions. The combination of liraglutide and insulin should be avoided if liraglutide is used exclusively for weight loss (Saxenda). Consider therapy modification

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

Maitake: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. 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. Consider therapy modification

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

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

Pioglitazone: May enhance the adverse/toxic effect of Insulins. Specifically, the risk for hypoglycemia, fluid retention, and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone, dose reductions should be considered to reduce the risk of hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure. Consider therapy modification

Pramlintide: May enhance the hypoglycemic effect of Insulins. Management: Upon initiation of pramlintide, decrease mealtime insulin dose by 50% to reduce the risk of hypoglycemia. Monitor blood glucose frequently and individualize further insulin dose adjustments based on glycemic control. Consider therapy modification

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

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

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

Rosiglitazone: Insulins may enhance the adverse/toxic effect of Rosiglitazone. Specifically, the risk of fluid retention, heart failure, and hypoglycemia may be increased with this combination. Avoid combination

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

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

Sodium-Glucose Cotransporter 2 (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. Consider therapy modification

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

Adverse Reactions

Incidence rates are from glargine administered with concomitant antidiabetic agents (insulin or oral products).

>10%

Cardiovascular: Hypertension (20%), peripheral edema (20%)

Central nervous system: Depression (11%)

Endocrine & metabolic: Severe hypoglycemia (Type I on combination regimens: 4% to 69%; Type II on combination regimens: ≤37%; monotherapy in adults ≥50 years old: 6% [ORIGIN trial])

Gastrointestinal: Diarrhea (11%)

Genitourinary: Urinary tract infection (11%)

Immunologic: Antibody development (12% to 44%)

Infection: Infection (9% to 24%), influenza (19%)

Neuromuscular & skeletal: Arthralgia (14%), back pain (13%), limb pain (13%)

Ophthalmic: Cataract (18%)

Respiratory: Upper respiratory tract infection (5% to 29%), sinusitis (19%), nasopharyngitis (6% to 16%), bronchitis (15%), cough (12%)

1% to 10%:

Cardiovascular: Retinal vascular disease (6%)

Central nervous system: Headache (6% to 10%)

Local: Pain at injection site (3%)

Respiratory: Pharyngitis (children and adolescents: 8%), rhinitis (children andadolescents: 5%)

Miscellaneous: Accidental injury (6%)

Frequency not defined:

Dermatologic: Urticaria at injection site

Endocrine & metabolic: Sodium retention, weight gain

Hypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction

Local: Erythema at injection site, hypertrophy at injection site, inflammation at injection site, itching at injection site, lipoatrophy at injection site, localized edema, swelling at injection site

Postmarketing: Amyloidosis (localized cutaneous at injection site)

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: Severe, life-threatening allergic reactions, including anaphylaxis, may occur. If hypersensitivity reactions occur, discontinue therapy.
• 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 early after these procedures (gastric bypass is most effective, followed by sleeve and finally band) (Korner 2009; Peterli 2012). Monitoring of hospital insulin requirements is recommended to guide discharge insulin dose. Rates and timing of type 2 diabetes improvement and resolution vary widely by patient; insulin dose reduction of 75% has been suggested after gastric bypass for patients without severe β-cell failure (fasting c-peptide <0.3 nmol/L) (Cruijsen 2014).

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

• Cardiac disease: Concurrent use with peroxisome proliferator-activated receptor (PPAR)-gamma agonists, including thiazolidinediones, may cause dose-related fluid retention and lead to or exacerbate heart failure (HF), particularly when used in combination with insulin. If PPAR-gamma agonists are prescribed, monitor for signs and symptoms of HF. If HF develops, consider PPAR-gamma agonist dosage reduction or therapy discontinuation.
• Diabetic ketoacidosis: Should not be used in patients with diabetic ketoacidosis (DKA); use of an IV rapid acting or short acting insulin is preferred.
• Hepatic impairment: Use with caution in patients with hepatic impairment. Dosage requirements may be reduced.
• Renal impairment: Use with caution in patients with renal impairment. Dosage requirements may be reduced.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Hospitalized patients with diabetes: Exclusive use of a sliding scale insulin regimen (insulin regular) in the inpatient hospital setting is strongly discouraged. In the critical care setting, continuous IV insulin infusion (insulin regular) has been shown to best achieve glycemic targets. In noncritically ill patients with either poor oral intake or taking nothing by mouth, basal insulin or basal plus bolus is preferred. In noncritically ill patients with adequate nutritional intake, a combination of basal insulin, nutritional, and correction components is preferred. An effective insulin regimen will achieve the goal glucose range without the risk of severe hypoglycemia. A blood glucose value <70 mg/dL should prompt a treatment regimen review and change, if necessary, to prevent further hypoglycemia (ADA 2019).

Dosage form specific issues:

• Multiple dose injection pens: According to the Centers for Disease Control and Prevention (CDC), pen-shaped injection devices should never be used for more than one person (even when the needle is changed) because of the risk of infection. The injection device should be clearly labeled with individual patient information to ensure that the correct pen is used (CDC 2012).

Other warnings/precautions:

• Administration: Insulin glargine is a clear solution, but it is NOT intended for IV or IM administration or via an insulin pump.
• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of 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]), potassium (in patients at risk for hypokalemia); lipid profile; 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).

Pregnancy

Pregnancy Considerations

Because insulin glargine has an increased affinity to the insulin-like growth factor (IGF-I) receptor, there are theoretical concerns that it may contribute to adverse events when used during pregnancy (Blumer 2013).

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. 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). Pregnancy outcomes are similar following maternal use of insulin glargine and NPH insulin in pregnant females with type 1 diabetes mellitus. Outcomes are likely to be similar in pregnant females with type 2 diabetes and insulin glargine may be used when clinically indicated (ACOG 201 2018).

Females with diabetes mellitus who wish to conceive should use adequate contraception until glycemic control is achieved (ADA 2020). Females who are stable on insulin glargine prior to conception may continue it during pregnancy. Theoretical concerns of insulin glargine should be discussed prior to conception (Blumer 2013).

Patient Education

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
• Back pain
• Diarrhea
• Headache
• Common cold symptoms
• Joint pain
• Painful extremities
• Nose irritation
• Throat 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, a fast heartbeat, confusion, hunger, or sweating.
• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat.
• Infection
• Vision changes
• Severe dizziness
• Passing out
• Seizures
• Shortness of breath
• Excessive weight gain
• Swelling of arms or legs
• Depression
• 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.