AHFS Class:

• Long-acting Insulins 68:20.08.16

Generic Name(s):

• Insulin Detemir

Because this drug is no longer available in the U.S. market, the material in this section is no longer updated by AHFS DI. If this drug is used in countries other than the U.S., it is essential that the manufacturers' labeling be consulted for more recently available information.

Insulin detemir is a biosynthetic (rDNA origin), long-acting human insulin analog that is prepared using a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification.1,18

Because this drug is no longer available in the U.S. market, the material in this section is no longer updated by AHFS DI. If this drug is used in countries other than the U.S., it is essential that the manufacturers' labeling be consulted for more recently available information.

Diabetes Mellitus

Insulin detemir is used to improve glycemic control in the management of type 1 or type 2 diabetes mellitus in patients who require a long-acting insulin.1,2,3,4,5 Insulin detemir appears to be at least as effective for glycemic control in adults with diabetes mellitus as isophane (NPH) insulin or insulin glargine (as determined by glycosylated hemoglobin [hemoglobin A_1c, HbA_1c] and fasting plasma glucose values).1,2,3,7,16,18 Current evidence suggests that insulin detemir may be associated with less interindividual variability in fasting blood glucose concentrations2,7,10,16,17,22,23 and a lower risk of hypoglycemia2,7,16,17,22,23 and weight gain1,2,7,16,17,22 than isophane insulin.17,18 Less variability in the pharmacodynamic effects of insulin detemir may facilitate more optimal adjustment of basal insulin dosage without an increased risk of hypoglycemia.2,3,5,7,10,16,17,22,23,24 Insulin detemir may provide advantages over isophane insulin in patients with diabetes mellitus who have had difficulty achieving adequate glycemic control without frequent hypoglycemic episodes and/or those at high risk of hypoglycemia, particularly nocturnal hypoglycemia.16,17,23

Safety and efficacy of insulin detemir compared with isophane insulin human for the treatment of type 1 diabetes mellitus have been demonstrated in several randomized, open-label, noninferiority studies of up to 26 weeks' duration in adults.1,2,3,4,7,16 In these studies, patients received basal insulin once or twice daily in conjunction with insulin human (regular) or insulin aspart as premeal insulin.1,2,3,4,7,16 A preliminary report suggests that glycemic control with insulin detemir is maintained at 24 months in adults with type 1 diabetes mellitus.25 Safety and efficacy of insulin detemir compared with isophane insulin human in pediatric patients 2-17 years of age with type 1 diabetes mellitus also have been demonstrated in 2 randomized, open-label studies of 26 or 52 weeks' duration in which the basal insulins were administered once or twice daily with premeal insulin aspart.1,10,30 (See Pediatric Use under Warnings/Precautions: Special Populations, in Cautions.) In the 26-week study, therapy with insulin detemir generally resulted in similar reductions in HbA_1c as isophane insulin but was associated with less weight gain and a lower risk of nocturnal hypoglycemia.1,2,3,4,10,22,23 Fasting plasma glucose concentrations with insulin detemir therapy were similar to or lower than those achieved with isophane insulin;2,3,4,7 however, target fasting blood glucose concentrations (e.g., 72-126 mg/dL) were not achieved in some studies,2,3,4 possibly because of insufficient titration of basal insulin dosage.2,4,17 In the 52-week study, insulin detemir was noninferior to isophane insulin human in terms of glycemic control (as determined by HbA_1c); however, a slight increase in HbA_1c was observed in both treatment groups.1,30 The observed increase in HbA_1c was principally attributable to the suboptimal glycemic control in the subgroup of patients 13-16 years of age.36 This increase may be explained in part by the difficulties of treating children for whom many factors (e.g., hormonal changes and growth, social status, variable lifestyles, fear of hypoglycemia) influence glycemic control.30,36 Therapy with insulin detemir also was associated with less weight gain and a lower risk of 24-hour and nocturnal hypoglycemia.30

Some evidence also indicates similar glycemic control with insulin detemir and insulin glargine in adults with type 1 diabetes mellitus.1,4,19 In a randomized, open-label, noninferiority study, reductions in HbA_1c at 26 weeks were similar in adults with type I diabetes mellitus who received either twice-daily (morning and bedtime) insulin detemir or once-daily (bedtime) insulin glargine as basal insulin therapy in conjunction with premeal insulin aspart therapy.1,4,19 Target prebreakfast (fasting) plasma glucose concentrations (less than 132 mg/dL) were achieved more often with insulin glargine than with insulin detemir in this study, probably because of the effects of the entire daily insulin glargine dose being administered at bedtime.4,19 Body weight gain was similar in both treatment groups.19 Overall, the risk of hypoglycemia was similar in both treatment groups, but the risk of severe and nocturnal hypoglycemia was lower with insulin detemir than with insulin glargine.19

Safety and efficacy of insulin detemir administered once or twice daily in adults with type 2 diabetes mellitus have been established in 2 open-label, randomized clinical studies of 22 or 24 weeks' duration that compared insulin detemir with isophane insulin human administered once or twice daily.1,5,11 In a noninferiority study in insulin-naive patients with type 2 diabetes mellitus who were inadequately controlled with oral antidiabetic therapy, twice-daily therapy with insulin detemir or isophane insulin human was added to existing therapy with 1 or 2 oral antidiabetic agents (metformin, insulin secretagogue, and/or α-glucosidase inhibitor).1,4,11,18 Insulin detemir and isophane insulin human provided similar improvements in glycemic control (as measured by HbA_1c, the primary clinical end point) in this study.1,11,18 The proportion of patients attaining target HbA_1c values of 7% or less at study end point was similar across treatment groups.11 Basal insulin doses were titrated to achieve prebreakfast and predinner target blood glucose concentrations; an increased dosage of insulin detemir (0.77 units/kg) compared with that of insulin isophane human (0.52 units/kg) was required to achieve similar glycemic control.4,11 The risk of hypoglycemia, particularly nocturnal hypoglycemia, was reduced with insulin detemir compared with that observed with isophane insulin human; less weight gain was observed with insulin detemir than with isophane insulin human.11,17,18 In another comparative study in patients with type 2 diabetes mellitus previously receiving insulin or a combination of oral antidiabetic agents and insulin, insulin detemir and isophane insulin human provided similar glycemic control (as measured by HbA_1c).1,4,5,7 Insulin aspart or insulin human (regular) was given as the mealtime insulin in patients treated with insulin detemir or isophane insulin human, respectively.1,4,5,7,18 Basal insulin was given once or twice daily, based on the patient's prestudy insulin regimen (basal and preprandial insulin, biphasic insulin, or insulin and oral antidiabetic agents); oral antidiabetic agents were discontinued at study entry.4,5 Basal and mealtime insulin doses were titrated to achieve fasting, preprandial, and postprandial target plasma glucose concentrations of less than 107 mg/dL, 90-125 mg/dL, and 161 mg/dL or less, respectively; if these target plasma glucose concentrations were not met with a once-daily basal insulin regimen, patients were transferred to a twice-daily basal insulin regimen.5 (See Transferring from Therapy with Other Insulins under Dosage: Diabetes Mellitus, in Dosage and Administration.)

When given as add-on therapy to metformin and liraglutide in a clinical study, insulin detemir further improved glycemic control as determined by HbA_1c and fasting plasma glucose concentrations.1,31 Efficacy and safety of insulin detemir as add-on therapy with liraglutide and metformin were established in a 26-week, open-label study in patients with inadequate glycemic control while receiving metformin alone or in combination with a sulfonylurea.1,31 In this study, all patients entered a 12-week run-in period during which patients continued metformin therapy and received add-on therapy with liraglutide titrated to 1.8 mg once daily.1,31 Therapy with sulfonylureas was discontinued at the start of the run-in period.1,31 At the end of the run-in period, approximately 50% of patients had achieved the target HbA_1c of less than 7%.1 Compared with patients who did not reach the target HbA_1c during the run-in period, those who did reach the target HbA_1c had a shorter duration of type 2 diabetes mellitus, lower initial HbA_1c and fasting plasma glucose concentrations, and more had been treated with only metformin before study enrollment.31 Patients with HbA_1c values of 7% or greater (excluding those who withdrew from the study) received 26 weeks of once-daily insulin detemir administered in the evening as add-on therapy or continued unchanged treatment with liraglutide and metformin.1,31 The addition of insulin detemir to liraglutide and metformin therapy resulted in clinically relevant further reductions of HbA_1c compared with continued, unchanged treatment with liraglutide and metformin alone (reduction of 0.5 versus 0%, respectively, in HbA_1c).1,31 Mean fasting blood glucose concentrations decreased more in the insulin detemir add-on therapy group than with metformin and liraglutide alone (decrease of 38 and 7 mg/dL, respectively).1,31 Additionally, a greater percentage of patients in the add-on therapy insulin detemir treatment group achieved an HbA_1c of less than 7% compared with the liraglutide and metformin alone treatment group (43 versus 17% of patients, respectively).1,31 There was a mean weight reduction of 0.3 or 1.1 kg in the patients who received insulin detemir add-on therapy or unchanged treatment with liraglutide and metformin alone, respectively.1 Patients who received add-on therapy with insulin detemir maintained the substantial weight reduction achieved during the liraglutide run-in period rather than gaining weight as typically occurs with insulin therapy.31

Insulin detemir, a long-acting basal insulin, is not indicated for the treatment of diabetic ketoacidosis; a short-acting insulin (e.g., regular insulin) is the preferred agent.1,17,18,20

General

Because this drug is no longer available in the U.S. market, the material in this section is no longer updated by AHFS DI. If this drug is used in countries other than the U.S., it is essential that the manufacturers' labeling be consulted for more recently available information.

Dosage of insulin detemir is expressed in units.1 Each unit of insulin detemir is approximately equal to 0.142 mg of the drug.1

Dosage of insulin detemir based on the results of blood glucose determinations and carefully individualized to obtain optimum therapeutic effect.1 Glucose monitoring is recommended for all patients with diabetes mellitus.1

Administration

Insulin detemir is administered by subcutaneous injection once or twice daily using a conventional insulin syringe or FlexTouch^® injection pen.1

The prolonged duration of action of soluble insulin detemir is dependent in part on slow systemic absorption (e.g., secondary to albumin binding).1,2,3,4,5,6,7,18,22,23 (See Description.) Insulin detemir should not be given IV or IM, nor should it be given via an insulin infusion pump.1 Insulin detemir is absorbed more rapidly and more extensively following IM or IV administration than when it is given subcutaneously.6,17 IV administration of the usual subcutaneous dosage of insulin detemir could result in severe hypoglycemia.1,17 Insulin detemir is administered by subcutaneous injection into the thigh, abdominal wall, or upper arm.1 A planned rotation of sites within an area should be followed.1 Insulin detemir should not be mixed with any other insulin or solution, as such mixing may result in unpredictable alterations in the pharmacokinetic and/or pharmacodynamic characteristics (e.g., onset of action, time to peak effect) of insulin detemir and/or the mixed insulin.1,6,7,17,18

When the FlexTouch^® injection pen is used for subcutaneous injection of insulin detemir, the accompanying labeling should be consulted for proper methods of administration and care.1,8,18 The FlexTouch^® injection pen is used with NovoFine^®, NovoFine Plus^®, or NovoTwist^® needles.8

When insulin detemir is given once daily, the daily dose should be administered with the evening meal or at bedtime.1,7 However, insulin detemir also has been administered once daily in the morning† in patients with type 2 diabetes mellitus.18,21 For patients who require twice-daily doses of insulin detemir (i.e., predinner blood glucose concentrations above the target blood glucose concentration), the first dose may be administered in the morning and the second dose may be administered after the evening meal, at bedtime, or 12 hours after the morning dose.1,3,7

When insulin detemir is used in conjunction with a glucagon-like peptide-1 (GLP-1) receptor agonist, the drugs should be administered as separate injections; these injections should not be mixed.1 Insulin detemir and the GLP-1 receptor agonist may be injected into the same body region; however, the injections should not be adjacent to each other.1

Unopened insulin detemir injection pens and vials should be protected from light and stored in the original carton at 2-8°C until the expiration date; the drug should not be frozen.1 Insulin detemir should not be stored directly adjacent to the refrigerator cooling element; insulin detemir should not be used if freezing has occurred.1 Alternatively, if refrigeration is not possible, unopened insulin detemir injection pens and vials may be stored at room temperature and away from direct heat and light for up to 42 days.1 Opened (in-use) insulin detemir vials should be stored at 2-8°C.1 Alternatively, if refrigeration is not possible, in-use insulin detemir vials may be stored at room temperature away from direct heat and light for up to 42 days.1 In-use insulin detemir injection pens should be stored at room temperature away from heat and direct light for up to 42 days; in-use injection pens should not be refrigerated or stored with the needle attached.1

Dosage

Diabetes Mellitus

Because of its long duration of action, insulin detemir is used alone as a basal insulin (e.g., insulin-naive patients) or concomitantly with a shorter-acting (“bolus”) insulin (e.g., insulin aspart, insulin human) to provide more optimal postprandial glycemic control.1,7 When used in a meal-related subcutaneous insulin regimen, the initial insulin detemir dosage should be approximately one-third of the total daily insulin dosage, with the remainder given preprandially as a rapid- or short-acting insulin.1 Initial total daily insulin dosages in adults and children with type 1 diabetes mellitus generally range from 0.2-1 unit/kg. The dosage of insulin detemir should be increased until the desired fasting plasma glucose concentrations are achieved.1,7

In comparative clinical studies of short duration (16 weeks to 6 months) in adults with type 1 diabetes mellitus, the mean total daily dosage of insulin detemir or isophane insulin human at the completion of the study was 0.27-0.45 units/kg or 0.33-0.38 units/kg, respectively. 34

In a comparative clinical study in pediatric patients 6-17 years of age with type 1 diabetes mellitus, the mean total daily dosage of insulin detemir or isophane insulin human at completion of the study was 0.67 or 0.64 units/kg, respectively, and the total daily dosage of insulin aspart given preprandially was 0.52 units/kg.10,18

In insulin-naive adults with type 2 diabetes mellitus who are inadequately controlled with oral antidiabetic agents, the recommended initial dosage of insulin detemir is 10 units (or 0.1-0.2 units/kg) given once daily in the evening or divided into a twice-daily regimen, with subsequent dosage adjusted to achieve glycemic goals.1 Close monitoring of blood glucose concentrations is recommended during the transition to insulin detemir and in the initial weeks thereafter.1

In adults with type 2 diabetes mellitus with inadequate glycemic control while receiving a glucagon-like peptide-1 (GLP-1) receptor agonist, the recommended initial dosage of insulin detemir is 10 units given once daily in the evening, with subsequent dosage adjustments to achieve glycemic goals.1 When a GLP-1 receptor agonist is used in conjunction with insulin detemir, a reduction in the dosage of insulin detemir, or more conservative titration, may be required to minimize the risk of hypoglycemia.1

The dosage and timing of concurrent short- or rapid-acting insulins or other concomitant antidiabetic agents may need to be adjusted.1,18 Insulin requirements may be altered during illness, emotional disturbances, or other stresses.1

Transferring from Therapy with Other Insulins

When insulin detemir is substituted for another intermediate- or long-acting insulin in patients with diabetes mellitus receiving combination therapy with a short- or rapid-acting insulin and a longer-acting insulin, the initial dosage of insulin detemir can be identical (on a unit-for-unit basis) to the dosage of the previous longer-acting insulin.1 The dosage of insulin detemir should then be adjusted according to blood glucose determinations to achieve glycemic goals.1,17 In patients currently receiving a basal insulin only, insulin detemir may be substituted on a unit-for-unit basis for the basal insulin currently in use.1 Some patients with type 2 diabetes mellitus who are switched from isophane insulin human may require a higher dosage of insulin detemir.1,4 Close monitoring of blood glucose concentrations is recommended during the transition to insulin detemir and in the initial weeks thereafter.1 The dosage and timing of concurrent short- or rapid-acting insulin or other concomitant antidiabetic agents may need to be adjusted.1

Special Populations

In a pharmacokinetic study in patients with or without renal impairment (mild to severe renal impairment, some patients requiring hemodialysis) who received a single subcutaneous dose of insulin detemir, the pharmacokinetic parameters in renally impaired patients were no different that those in healthy individuals.1,6,18 However, since clearance of insulin human has been decreased in patients with renal impairment, blood glucose concentrations should be monitored carefully, and adjustment of insulin detemir dosage may be necessary in such patients.1

In patients with hepatic impairment, the area under the concentration-time curve (AUC) of insulin detemir decreased with increasing degrees of hepatic impairment.1,6 However, some studies conducted with human insulin in patients with hepatic impairment have shown increased circulating levels of insulin.1 Blood glucose concentrations should be monitored carefully, and adjustment of insulin detemir dosage may be necessary in such patients.1

In geriatric patients, the initial dosage, dose increments, and maintenance dosage should be conservative in order to avoid hypoglycemia.1

Based on preliminary data, dosage adjustments in children or adolescents based solely on age do not appear to be necessary.7

Contraindications

Because this drug is no longer available in the U.S. market, the material in this section is no longer updated by AHFS DI. If this drug is used in countries other than the U.S., it is essential that the manufacturers' labeling be consulted for more recently available information.

Known hypersensitivity to insulin detemir or any ingredient in the formulation.1

Warnings/Precautions

Hypoglycemia

Hypoglycemia is the most common adverse effect of insulins, including insulin detemir, and monitoring of blood glucose concentrations is recommended for all patients with diabetes mellitus.1 The prolonged effect of subcutaneous insulin detemir may delay recovery from hypoglycemia.1 Severe hypoglycemia requiring the assistance of another person, IV glucose infusions, or glucagon administration has occurred with insulin therapy, including insulin detemir.1 As with all insulin preparations, the time course of the glucose-lowering effect of insulin detemir may vary among different individuals or at different times in the same individual and depends on many conditions (e.g., area of injection, injection site blood supply and temperature).1 The risk of hypoglycemia generally increases with the intensity of glycemic control.1 Other factors that may increase a patient's risk of hypoglycemia include changes in meal patterns, level of physical activity, or coadministered drugs.1 The onset of hypoglycemia depends on the action profile of the insulins used and may change when the treatment regimen or timing of dosing of the insulins is changed.1 (See Transferring from Therapy with Other Insulins under Dosage and Administration: Dosage.) Some evidence suggests that insulin detemir may be associated with a lower risk of hypoglycemia, particularly nocturnal hypoglycemia, than isophane insulin.2,7,16,17,22,23 In comparative studies, the incidence of severe hypoglycemic reactions with insulin detemir was similar to that with isophane insulin human.1,2,3,5,22 In a comparative study with insulin glargine, the incidence of severe and nocturnal hypoglycemia was lower with insulin detemir.19 (For more information on the symptoms associated with hypoglycemia, See Hypoglycemia under Cautions: Endocrine and Metabolic Effects, in the Insulins General Statement 68:20.08.)

Formulation Considerations

Any change in insulin should be made cautiously and only under medical supervision.1 Insulin detemir should not be diluted or mixed with any other insulin.1,6,18 Patients previously receiving insulin may require a change in dosage if insulin therapy is changed to insulin detemir.1 Likewise, adjustment of oral antidiabetic dosage may be necessary in patients receiving concomitant therapy with insulin detemir.1 Changes in insulin strength, manufacturer, timing of dosing, type, and/or method of manufacture may necessitate a change in insulin dosage.1,18 (See Transferring from Therapy with Other Insulins under Dosage and Administration: Dosage.)

Sharing of Injection Pens

Insulin detemir injection pens must never be shared among patients, even if the needle has been changed.1 Sharing of injection pens poses a risk for transmission of blood-borne pathogens.1

Metabolic Effects

Insulin may cause sodium retention and edema, particularly if metabolic control is improved by intensive insulin therapy.1 Insulin therapy, including insulin detemir, also may cause weight gain attributable to the anabolic effects of insulin and the decrease in glucosuria.1

Heart Failure

Peroxisome proliferator-activated receptor (PPAR)-γ agonists (e.g., thiazolidinediones) can cause dose-related fluid retention, particularly when used in combination with insulin.1,32,33 Fluid retention may lead to or exacerbate heart failure.1,32,33 Patients treated with insulin, including insulin detemir, and a PPAR-γ agonist should be observed for manifestations of heart failure (e.g., excessive/rapid weight gain, shortness of breath, edema).1,32 If heart failure develops, it should be managed according to current standards of care and discontinuance or dose reduction of the PPAR-γ agonist must be considered.1,32 Concomitant use of rosiglitazone and insulin therapy is not recommended.33

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity with insulin detemir.1 Insulin antibodies may increase or decrease the efficacy of insulin and insulin dosage adjustments may be required.1 During phase 3 clinical trials of insulin detemir, antibody development has been observed with no apparent impact on glycemic control.1

Sensitivity Reactions

Dermatologic and Sensitivity Reactions

As with any insulin therapy, lipodystrophy may occur at sites of insulin injections and may delay insulin absorption.1,7,18 Localized allergic reactions (e.g., pruritus, erythema, swelling, urticaria) at the injection site may develop in patients receiving insulins, including insulin detemir.1,4,12,13,14,15 Pain,1,13,14,15 inflammation,1,13,15 and subcutaneous nodules12,14,15 at the injection site also have been reported.1,13 These reactions generally are relatively minor and usually resolve within a few days to a few weeks1,14,15 but rarely may be severe13 and require discontinuance of insulin detemir.1,12,13 Poor injection technique or irritants in skin cleansing agents may contribute to localized injection site reactions;1 it also has been theorized that the myristic acid moiety of insulin detemir may be allergenic in some patients.15 Injection site rotation within an area may reduce or prevent these effects in some1 but not all13 cases.

Generalized hypersensitivity to insulin, characterized by whole-body rash, pruritus, shortness of breath, wheezing, hypotension, tachycardia, and diaphoresis, has occurred less frequently than localized reactions.1 Severe cases of generalized insulin allergy with anaphylaxis may be life-threatening.1

Specific Populations

Pregnancy

Category B.1 (See Users Guide.)

In an open-label clinical study of pregnant women with type 1 diabetes mellitus, insulin detemir therapy did not increase the risk of fetal abnormalities compared with isophane (NPH) insulin human.1,38 Additionally, there was no difference in pregnancy outcomes or the health of the fetus and newborn with insulin detemir use.1 Studies in rats and rabbits indicate that insulin detemir and human insulin have similar embryotoxic and teratogenic effects, which may be attributable to maternal hypoglycemia.1

Lactation

Not known whether insulin detemir is distributed into milk.1 Caution is advised if used in nursing women.1 Diabetic women who are lactating may require adjustments in insulin detemir dosage, meal plans, or both.1

Pediatric Use

The safety and efficacy of insulin detemir compared with isophane insulin human have been demonstrated in 2 randomized, open-label studies of 26 or 52 weeks' duration in children and adolescents 2-17 years of age with type 1 diabetes mellitus; children also received insulin aspart as the preprandial insulin.1,10,30 Insulin detemir and isophane insulin human provided similar glycemic control (as determined by glycosylated hemoglobin [hemoglobin A_1c, HbA_1c]) in these studies.1,10,30 Safety and efficacy of insulin detemir in pediatric patients with type 2 diabetes mellitus have not been established.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1 Pharmacokinetic data indicate a higher exposure (increased area under the concentration-time curve) for insulin detemir among geriatric patients compared with young adults, as a result of decreased clearance of the drug.1,6 Initial dosage, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia.1 Hypoglycemia may be difficult to recognize in geriatric patients.1

Hepatic Impairment

Blood glucose concentrations should be monitored closely; adjustment of insulin detemir dosage may be necessary.1 (See Dosage and Administration: Special Populations.)

Renal Impairment

Blood glucose concentrations should be monitored closely; adjustment of insulin detemir dosage may be necessary.1 (See Dosage and Administration: Special Populations.)

Common Adverse Effects

Common adverse effects associated with insulin detemir include hypoglycemia,1,2,3,5,11 allergic reactions,1 pruritus,1,5 rash,1,5 injection site reactions,1,5,11 lipodystrophy,1 peripheral edema,1 and weight gain.1,5,11 Additional adverse effects occurring in at least 5% of adults receiving insulin detemir for the management of type 1 or type 2 diabetes mellitus in clinical trials of 16-26 weeks' duration include upper respiratory tract infection,1 headache,1 pharyngitis,1 influenza-like illness,1 abdominal pain,1 back pain,1 gastroenteritis,1 and bronchitis.1

Adverse effects occurring in at least 5% of pregnant women receiving insulin detemir for the management of type 1 diabetes mellitus include anemia,1 diarrhea,1 preeclampsia,1 urinary tract infection,1 gastroenteritis,1 upper abdominal pain,1 vomiting,1 spontaneous abortion,1 abdominal pain,1 and oropharyngeal pain.1

Adverse effects occurring in at least 5% of children and adolescents receiving insulin detemir for the management of type 1 diabetes mellitus in a clinical trial of 26 weeks' duration include upper respiratory tract infection,1 headache,1 pharyngitis,1 gastroenteritis,1 influenza-like illness,1 abdominal pain,1 pyrexia,1 cough,1 viral infection,1 nausea,1 rhinitis,1 and vomiting.1

Because this drug is no longer available in the U.S. market, the material in this section is no longer updated by AHFS DI. If this drug is used in countries other than the U.S., it is essential that the manufacturers' labeling be consulted for more recently available information.

Drugs Affecting Glycemic Control

Drugs that May Potentiate Hypoglycemic Effects

Angiotensin-converting enzyme (ACE) inhibitors, disopyramide, fibrate derivatives, fluoxetine, monoamine oxidase (MAO) inhibitors, oral antidiabetic agents, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), sulfonamide anti-infectives.1,18

Drugs that May Antagonize Hypoglycemic Effects

Atypical antipsychotics (e.g., olanzapine, clozapine),1 corticosteroids,1,16 danazol,1 diuretics,1,16 estrogens or progestins (e.g., oral contraceptives),1 glucagon,1 isoniazid,1 niacin,1,26 phenothiazines,1 protease inhibitors,1 somatropin,1 sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline),1 thyroid hormones.1,18

Drugs that May Have a Variable Effect of Glycemic Control

Alcohol,1β-adrenergic blocking agents,1,16 clonidine,1 lithium salts,1 pentamidine.1

Sympatholytic Agents

May decrease or eliminate the signs of hypoglycemia in patients receiving insulin detemir concomitantly with these drugs (e.g., β-adrenergic blocking agents, clonidine, guanethidine, reserpine).1

Glucagon-like Peptide 1 Receptor Agonists

No pharmacokinetic interaction was observed following administration of single-dose subcutaneous injections of insulin detemir (0.5 units/kg) during steady-state liraglutide therapy (titrated to a 1.8-mg daily dosage over 3 weeks) in patients with type 2 diabetes mellitus.1,35 However, an additive glucose-lowering effect was observed.1,35 When a GLP-1 receptor agonist (e.g., liraglutide) is used concomitantly with insulin detemir, a reduction in the dosage of insulin detemir, or more conservative dosage titration, may be required to minimize the risk of hypoglycemia.1

Peroxisome Proliferator-activated Receptor- Agonists

Peroxisome proliferator-activated receptor (PPAR)-γ agonists (e.g., thiazolidinediones) can cause dose-related fluid retention, particularly when used in conjunction with insulin.1,32,33 Fluid retention may lead to or exacerbate heart failure.1,23,24 Patients treated with insulin, including insulin detemir, and a PPAR-γ agonist should be observed for manifestations of heart failure (e.g., excessive/rapid weight gain, shortness of breath, edema).1,32 (See Heart Failure under Cautions: Warnings/Precautions.)

Protein-bound Drugs

No clinically relevant in vivo or in vitro interaction with other protein-bound drugs.1,18

Description

Because this drug is no longer available in the U.S. market, the material in this section is no longer updated by AHFS DI. If this drug is used in countries other than the U.S., it is essential that the manufacturers' labeling be consulted for more recently available information.

Insulin detemir is a biosynthetic (rDNA origin), long-acting insulin human analog that is prepared using a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification.1,18 Insulin detemir differs structurally from insulin human by the deletion of threonine at position 30 on the B chain and by the acylation of lysine at position 29 on the B chain with myristic acid, a 14-carbon fatty acid.1,2,3,5 The prolonged (up to 24 hours) duration of action of insulin detemir appears to result from slow systemic absorption of the drug from the injection site and delayed distribution to target tissues.1,2,3,5,7,18 The fatty acid side chain modification of insulin detemir increases self-association of the drug molecules and reversible binding to albumin at the injection site.1,2,3,5,7,18 Once absorbed systemically, insulin detemir also is strongly (greater than 98%) bound to circulating albumin, which delays the distribution of the drug to target tissues and prolongs its action.1,6,7,18 Insulin detemir is soluble at neutral pH and the subcutaneous depot of the drug remains liquid; therefore, absorption of the drug is expected to occur with less variability than with other basal insulins.2,3 7 Insulin detemir has a longer duration of action than isophane insulin human, and insulin detemir therapy is associated with less intrapatient variability in blood glucose concentrations than therapy with isophane insulin human.1,2,4,5,7,9,11

Interindividual and intraindividual variation in rate of absorption and consequently, the onset of action of insulins, including insulin detemir, may occur based on site of injection, tissue blood supply, temperature, and physical activity.1

Advice to Patients

Because this drug is no longer available in the U.S. market, the material in this section is no longer updated by AHFS DI. If this drug is used in countries other than the U.S., it is essential that the manufacturers' labeling be consulted for more recently available information.

Provide copy of manufacturer's information for patients.1

Importance of informing patients that they should never share an insulin detemir injection pen with another person, even if the needle is changed; sharing of the pen may pose a risk of transmission of infection.1,8

Importance of informing patients that changes to insulin regimens should be made cautiously and only under medical supervision.1

Advise patients of the potential adverse effects of insulin therapy (e.g., hypoglycemia, weight gain, lipodystrophy [and the need to rotate injection sites], allergic reactions).1

Inform patients that the ability to concentrate and react may be impaired as a result of hypoglycemia, which may pose a risk in situations where these abilities are especially important (e.g., driving, operating machinery).1 Advise patients who experience frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery.1

Inform patients to always check the insulin container label prior to each injection; medication errors involving confusion between insulin detemir and other insulins (e.g., short-acting insulins) have occurred.1,8

Provide instructions regarding self-monitoring of blood glucose concentrations, injection technique, and management of hypoglycemia or hyperglycemia.1

Importance of not mixing insulin detemir with other insulins or solutions.1 Importance of using insulin detemir only if solution is clear and colorless with no visible particles.1,8

Discuss potential for alterations in insulin requirements in special situations (e.g., illness, emotional disturbances, or other stresses).1 Discuss potential for alterations in insulin requirements as a result of inadequate or skipped doses, inadvertent administration of an incorrect dose, inadequate food intake, or skipped meals.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Novo Nordisk. Levemir^® (insulin detemir) injection prescribing information. Plainsboro, NJ; 2015 Feb.

2. Russell-Jones D, Simpson R, Hylleberg B et al. Effects of QD insulin detemir or neutral protamine hagedorn on blood glucose control in patients with type 1 diabetes mellitus using a basal-bolus regimen. Clin Ther . 2004; 26:724-36.

3. Home P, Bartley P, Russell-Jones D et al. Insulin detemir offers improved glycemic control compared with NPH insulin in people with type 1 diabetes. Diabetes Care . 2004; 27:1081-7. [PubMed 15111525]

4. Misbin RI. Insulin detemir injection, Levemir^®: Medical review, FDA approval package. NDA number: 21-536. Rockville, MD: US Food and Drug Administration; 2005 Jun 16. (IDIS 453559)

5. Raslova K, Bogoev M, Raz I et al. Insulin detemir and insulin aspart: a promising basal-bolus regimen for type 2 diabetes. Diabetes Res Clin Pract . 2004; 66:193-201. [PubMed 15533587]

6. Wei X. Insulin detemir injection, Levemir^®. Clinical pharmacology and biopharmaceutics review, FDA approval package. NDA number: 21-536. Rockville, MD: US Food and Drug Administration; 2005 Jun 16.

7. Chapman TM, Perry CM. Insulin detemir: a review of its use in the management of type 1 and 2 diabetes mellitus. Drugs . 2004; 64:2577-95. [PubMed 15516157]

8. Novo Nordisk. Levemir^® FlexTouch^® Pen: Instructions for use. Plainsboro, NJ; 2015 Feb.

9. Plank J, Bedenlenz M, Sinner F et al. A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir. Diabetes Care . 2005; 28:1107-1112. [PubMed 15855574]

10. Robertson K, Schoenle E, Gucev Z et al. Insulin detemir compared with NPH insuln in children and adolescents with type 1 diabetes. Diabet Med . 2007; 24:27-34. [PubMed 17227321]

11. Hernamsen K, Davies M, Derezinski T et al. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care . 2006; 29:1269-74. [PubMed 16732007]

12. Darmon P, Castera V, Koeppel MC et al. Type III allergy to insulin detemir. Diabetes Care . 2005; 28:2980. Letter. [PubMed 16306568]

13. Blumer I. Severe injection site reaction to insulin detemir. Diabetes Care . 2006; 29:946. Letter. [PubMed 16567849]

14. Stechemesser L, Hofmann M, Hawranek T et al. Type III allergy to insulin detemir. Diabetes Care . 2006; 29:2758. Letter. [PubMed 17130222]

15. Sola-Gazagnes A, Pecquet C, M'Bemba J et al. Type I and type IV allergy to the insulin analogue detemir. Lancet . 2007; 369:637-8. Letter.

16. Jones MC, Patel M. Insulin detemir: a long-acting insulin product. AJHP . 2006; 63(Dec 15):2466-72. [PubMed 17158694]

17. Reviewers' comments (personal observations).

18. Novo Nordisk, Princeton, NJ: Personal communication.

19. Pieber TR, Treichel HC, Hompesch B et al. Comparison of insulin detemir and insulin glargine in subjects with type 1 diabetes using intensive insulin therapy. Diabet Med . 2007; 24:635-42. [PubMed 17381500]

20. Kitabchi AE, Umpierrez GE, Murphy MB et al. Hyperglycemic crises in adult patients with diabetes mellitus: a consensus statement from the American Diabetes Association. Diabetes Care . 2006; 29:2739-48. [PubMed 17130218]

21. Philis-Tsimikas A, Charpentier G, Clauson P et al. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes mellitus. Clin Ther . 2006; 28:1569-81.

22. Vague P, Selam JL, Skeie S et al. Insulin detemir is associated with more preducatable glycemic control and reduced risk of hypoglycemia than NPH insulin in patients with type 1 diabetes on a basal-blous regimen with premeal insulin aspart. Diabetes Car . 2003; 26:590-6.

23. Kolendorf K, Ross GP, Pavlic-Renart I et al. Insulin detemir lowers the risk of hypoglycemia and provides more consistent plasma glucose levels compared with NPH insulin in type 1 diabetes. Diabet Med . 2006; 23:729-35. [PubMed 16842476]

24. Heise T, Nosek L, Ronn BB et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes . 2004; 53:1614-20. [PubMed 15161770]

25. Bartley PC, Boroev M, Larsen J et al. Superior glycaemic control, less nocturnal hypoglycemia and less weight gain with insulin detemir relative to NPH insulin in subjects with T1DM treated for 24 months using a treat-to-target concept. Paper presented at the 43rd EASD annual meeting. Amsterdam: 2007 September 17-21. Abstract 222.

26. Abbott. Niaspan (niacin extended-release tablets) prescribing information. North Chicago, IL; 2007 Sep.

30. Thalange N, Bereket A, Larsen J et al. Insulin analogues in children with Type 1 diabetes: a 52-week randomized clinical trial. Diabet Med . 2013; 30:216-25. [PubMed 23094597]

31. DeVries JH, Bain SC, Rodbard HW et al. Sequential intensification of metformin treatment in type 2 diabetes with liraglutide followed by randomized addition of basal insulin prompted by A1C targets. Diabetes Care . 2012; 35:1446-54. [PubMed 22584132]

32. Takeda Pharmaceuticals America, Inc. Actos^® (pioglitazone) tablets prescribing information. Deerfield, IL; 2013 Nov.

33. GlaxoSmithKline. Avandia^® (rosiglitazone maleate) tablets prescribing information. Research Triangle Park, NC; 2014 May.

34. Keating GM. Insulin detemir: a review of its use in the management of diabetes mellitus. Drugs . 2012; 72:2255-87. [PubMed 23110609]

35. Morrow L, Hompesch M, Guthrie H et al. Co-administration of liraglutide with insulin detemir demonstrates additive pharmacodynamic effects with no pharmacokinetic interaction. Diabetes Obes Metab . 2011; 13:75-80. [PubMed 21114606]

36. Thalange N, Bereket A, Larsen J et al. Treatment with insulin detemir or NPH insulin in children aged 2-5 yr with type 1 diabetes mellitus. Pediatr Diabetes . 2011; 12:632-41. [PubMed 21418455]

37. Morales J. Defining the role of insulin detemir in Basal insulin therapy. Drugs . 2007; 67:2557-84. [PubMed 18034591]

38. Hod M, Mathiesen ER, Jovanovic L et al. A randomized trial comparing perinatal outcomes using insulin detemir or neutral protamine Hagedorn in type 1 diabetes. J Matern Fetal Neonatal Med . 2014; 27:7-13. [PubMed 23617228]