Insulin Detemir

Class: Insulins
VA Class: HS501
Chemical Name: 29B-[N6-(Oxo-tetradecy)-l-lysine]-(1A-21A),(1B-29B)-insulin (human)
Molecular Formula: C267H402N64O76S6
CAS Number: 169148-63-4
Brands: Levemir

Warning(s)

Special Alerts:

Novo Nordisk discontinued the sale of Levemir FlexPen (insulin detemir [rDNA origin] injection) on September 30, 2014. This action is not the result of any safety or performance issues related to Levemir FlexPen, but is due to the launch of Levemir FlexTouch. Patients do not need to return Levemir FlexPen if they have it on hand. The last shipment of Levemir FlexPen to the wholesalers was September 30, 2014. After this date and once the wholesaler's inventory is exhausted, no additional product will be available.

Introduction

Antidiabetic agent; long acting human insulin analog synthesized using recombinant DNA technology in Saccharomyces cerevisiae then chemically modified.1 18

Uses for Insulin Detemir

Diabetes Mellitus

Treatment of type 1 diabetes mellitus in adults and children ≥6 years of age or type 2 diabetes mellitus in adults who require long-acting (basal) insulin for control of hyperglycemia.1 2 3 4 5

Not indicated for the treatment of diabetic ketoacidosis; short-acting IV insulins (e.g., regular insulin) are preferred.17 18 20

At least as effective for glycemic control in adults as isophane insulin human or insulin glargine.1 2 3 7 16 18

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May be associated with less interindividual variability in fasting blood glucose concentration,2 7 10 16 17 22 23 lower risk for hypoglycemia,2 7 16 17 22 23 and a lower risk of weight gain1 2 7 16 17 22 than isophane insulin human.17 18 May provide advantages over isophane insulin human in patients 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 Additional study needed, especially in pediatric and geriatric patients.16 18 23

Insulin Detemir Dosage and Administration

Administration

Administer by sub-Q injection.1 18 Do not administer IV or IM or via insulin infusion pump.1 6 17

IV administration may cause severe hypoglycemia; prolonged duration of action dependent on sub-Q injection.a

Do not mix with any other insulin.1 6 7 17 18

Inspect visually prior to administration and use only if solution appears clear and colorless.a

Sub-Q Administration

Administer by sub-Q injection once or twice daily using a conventional insulin syringe, an injection pen (i.e., FlexPen or Innolet), or a PenFill cartridge-compatible insulin delivery device.8 18 a Use FlexPen and PenFill devices only with NovoFine needles.8 a

Consult labeling accompanying the injection device for proper assembly, administration, and care of injection pens and devices.1 8 18

Administer into thigh, abdominal wall, or upper arm.1 Follow a planned rotation of injection sites within an injection area.1

Once-daily regimen: Administer the daily dose with the evening meal or at bedtime.1 7 Has been administered once daily in the morning in patients with type 2 diabetes mellitus.18 21

Twice-daily regimen: Administer the first dose in the morning and the second dose after the evening meal, at bedtime, or 12 hours after the morning dose.1 3 7

Dosage

Dosage of insulin detemir is expressed in terms of USP units.1 b

Individualize dosage based on blood glucose determinations to obtain optimum therapeutic effect.1 Glucose monitoring is recommended for all patients with diabetes mellitus.1

Closely monitor blood glucose concentrations during insulin initiations and transitions and in the initial weeks thereafter.1 Adjust dosage and timing of insulins and/or other concomitant antidiabetic agents as needed to achieve glycemic goals.1 18

Make any dosage change cautiously and only under medical supervision.1 If insulin therapy is changed (e.g., strength, timing of dosing, manufacturer, type, or method of administration), may require adjustments in dosage of insulin detemir or concomitant antidiabetic agents.1 2 a

May require insulin dosage adjustment if patient changes usual physical activity or meal plan, or during times of illness, emotional disturbances, or stress.1

Pediatric Patients

Diabetes Mellitus

Children ≥6 years of age: Long duration of action; use 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 No specific dosage recommendations by manufacturer.a When used in a meal-related sub-Q insulin regimen, basal insulin requirements (e.g., insulin detemir) usually comprise 40–60% of the total daily insulin dosage, with the remainder given preprandially as rapid- or short-acting insulin.

Type 1
Sub-Q

Children ≥6 years of age: Initial total daily insulin dosages generally range from 0.2–1 unit/kg.

Transferring from Other Insulin Therapy
Sub-Q

Children ≥6 years of age, from combination therapy of intermediate- or long-acting and short- or rapid-acting insulin: Initial dosage of insulin detemir is identical (unit-for-unit basis) to the dosage of the longer-acting insulin.1

Children ≥6 years of age, from basal insulin only: Initial dosage of insulin detemir is identical (unit-for-unit basis) to the dosage of the basal insulin.1

Adults

Diabetes Mellitus

Long duration of action; use 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 sub-Q insulin regimen, basal insulin requirements (e.g., insulin detemir) usually comprise 40–60% of the total daily insulin dosage, with the remainder given preprandially as rapid- or short-acting insulin.

Insulin-naïve Patients
Sub-Q

Type 1: Initial total daily insulin dosages generally range from 0.2–1 unit/kg.

Type 2, inadequately controlled on oral antidiabetic agents: Initial dosage is 0.1–0.2 units/kg once daily in the evening or 10 units once or twice daily.1

Transferring from Other Insulin Therapy
Sub-Q

From combination therapy of intermediate- or long-acting and short- or rapid-acting insulin: Initial dosage of insulin detemir is identical (unit-for-unit basis) to the dosage of the longer-acting insulin.1

From basal insulin only: Initial dosage of insulin detemir is identical (unit-for-unit basis) to the dosage of the basal insulin.1

Some type 2 patients may require a higher dosage of insulin detemir than isophane insulin human.1 4

Special Populations

Hepatic Impairment

Dosage adjustment may be required in severe hepatic impairment (Child-Pugh grade C); carefully monitor blood glucose concentrations and adjust dosage as necessary.1 6 18 (See Hepatic Impairment under Cautions and also see Special Populations under Pharmacokinetics.)

Renal Impairment

Dosage adjustments may be required; carefully monitor blood glucose concentrations and adjust dosage as necessary.1 (See Renal Impairment under Cautions and also see Special Populations under Pharmacokinetics.)

Geriatric Patients

Conservative initial dosage, dose increments, and maintenance dosage recommended to avoid hypoglycemia.1 (See Geriatric Use under Cautions and also see Special Populations under Pharmacokinetics.)

Lactation

Dosage adjustments may be required.1 (See Specific Populations under Cautions.)

Cautions for Insulin Detemir

Contraindications

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

Warnings/Precautions

Warnings

Hypoglycemia

Most common adverse effect of insulins.1 Blood glucose concentration monitoring is recommended for all diabetic patients.1 Hypoglycemic timing may differ among various insulin formulations, and may change when the treatment regimen or timing of dosing of the insulins is changed.1

Rapid changes in serum glucose concentrations may precipitate manifestations of hypoglycemia, regardless of glucose concentrations. Early warning signs of hypoglycemia may be diminished or absent in patients with long-standing diabetes mellitus, diabetic neuropathy, intensified diabetes control, and/or those receiving drugs such as β-adrenergic blocking agents that mask catecholamine-induced manifestations of hypoglycemia (e.g., tremors, palpitations).a b Severe hypoglycemia (including loss of consciousness) may occur prior to patient’s awareness.a

Use intensive insulin therapy with caution in patients with a history of hypoglycemic unawareness or recurrent, severe hypoglycemic episodes. Higher target blood glucose concentrations (e.g., fasting blood glucose concentrations of 140 mg/dL and 2-hour postprandial concentrations of 200–250 mg/dL) are advisable in these patients.

Some evidence suggests that insulin detemir may be associated with a lower risk of nocturnal hypoglycemia than isophane insulin human or insulin glargine.2 7 16 17 19 22 23

Sensitivity Reactions

Hypersensitivity

Possible localized allergic reactions (e.g., pruritus, erythema, swelling, urticaria) at injection site.1 4 12 13 14 15 Usually resolves within a few days to a few weeks; 1 14 15 but, rarely, may require discontinuance of insulin detemir.1 12 13 May be related to other factors (e.g., irritants in skin cleansing agents, poor injection technique).1 Injection site rotation within an area may reduce or prevent these effects in some patients.1 13

Generalized hypersensitivity reactions (e.g., whole-body rash, pruritus, shortness of breath, wheezing, hypotension, tachycardia, diaphoresis, anaphylaxis) reported less frequently than localized reactions, but may be life-threatening. 1

General Precautions

Hyperglycemia

Possible hyperglycemia and, in type 1 patients, diabetic ketoacidosis with inadequate dosing or discontinuance of treatment.a First symptoms (e.g., nausea, vomiting, drowsiness, flushed dry skin, dry mouth, micturition frequency, thirst, loss of appetite, acetone breath) occur gradually over a period of hours or days.1 Untreated hyperglycemic events are potentially fatal.1

Lipodystrophy

Lipodystrophy may occur at injection sites of insulin injections and may delay insulin absorption;7 18 a injection site rotation may reduce or prevent these effects.1

Metabolic Effects

May cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensive insulin therapy.1

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether insulin detemir is distributed into milk; use caution in nursing women.1 (See Lactation under Dosage and Administration.)

Pediatric Use

Safety and efficacy not established in children <6 years of age.1

Geriatric Use

Response in patients ≥65 years of age does not appear to differ from that in younger adults; but increased sensitivity cannot be ruled out.1 Hypoglycemia may be difficult to recognize in geriatric patients.1 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Monitor blood glucose concentrations closely; dosage adjustment may be necessary.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Monitor blood glucose concentrations closely; dosage adjustment may be necessary.1 (See Renal Impairment under Dosage and Administration)

Common Adverse Effects

Hypoglycemia,1 2 3 5 11 pruritus,1 5 rash,1 5 injection site reactions,1 5 11 weight gain.1 5 11

Interactions for Insulin Detemir

Many drugs affect glucose metabolism; if such drugs are used concomitantly, may require insulin dosage adjustment and careful monitoring.a

Specific Drugs

Drugs That May Potentiate Hypoglycemic Effects

Alcohol1

ACE inhibitors1 18

Disopyramide1 18

Fibrate derivatives1 18

Fluoxetine1 18

Guanethidine1

MAO inhibitors1 18

Oral antidiabetic agents1 18

Propoxyphene1 18

Salicylates1 18

Somatostatin analogs (e.g., octreotide)1 18

Sulfonamide anti-infectives1 18

Drugs that May Antagonize Hypoglycemic Effects

Corticosteroids1 16

Danazol1

Diuretics1 16

Estrogens or progestins (e.g., oral contraceptives)1

Isoniazid1

Niacin26

Phenothiazines1

Somatropin1

Sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline)1

Thyroid hormones1 18

Drugs that May Have a Variable Effect on Glycemic Control

Alcohol1

β-Adrenergic blocking agents1 16

Clonidine1

Lithium salts1

Pentamidine1

Drugs That may Reduce or Eliminate Signs of Hypoglycemia (Sympatholytic Agents)

β-Adrenergic blocking agents1

Clonidine1

Guanethidine1

Reserpine1

Insulin Detemir Pharmacokinetics

Absorption

Bioavailability

Following sub-Q injection, absorption is slower and more prolonged than isophane insulin human.a

Following sub-Q injection, absolute bioavailability is 60%.a

Interindividual and intraindividual variation may occur based on site of injection, tissue blood supply, temperature, and physical activity.1

Absorption occurs with less variability than with other basal insulins.2 3 7

Atrophy or hypertrophy of subcutaneous fat tissue at the injection site may delay absorption.a

Duration

Dose dependent; 5.7–23.2 hours.a 50% of maximum effect occurs within 3–14 hours of administration.a

Special Populations

Children 6–12 years of age: slightly increased AUC and maximum serum concentration compared with adolescents and adults; values similar to those of isophane insulin human.a

Adolescents 13–17 years of age: No pharmacokinetic differences compared with adults.a

In geriatric patients, increased AUC.a (See Special Populations under Elimination.)

In severe hepatic dysfunction in nondiabetics, decreased AUC.a (See Special Populations under Dosage and Administration and also see Hepatic Impairment under Cautions.)

Distribution

Extent

Not known whether insulin detemir is distributed into milk.1

Plasma Protein Binding

>98% (mainly albumin).a

Elimination

Half-life

Terminal half-life: 5–7 hours.a

Special Populations

In geriatric patients, clearance is decreased.a (See Special Populations under Absorption.)

In renal impairment, no difference in pharmacokinetic parameters.a However, clearance of human insulin is decreased in renally impaired patients.a (See Special Populations under Dosage and Administration and see Renal Impairment under Cautions.)

Stability

Storage

Parenteral

Injection

Unopened vials, cartridges, Flexpen, and InnoLet: 2–8°C; store in carton to protect from light.a Do not freeze; discard if freezing occurs.a May keep at <30°C for ≤42 days.a

Opened (in-use) vials: 2 to <30°C for ≤42 days.a Protect from direct heat and light.a

Opened (in-use) cartridges, Flexpen, and InnoLet: <30°C for ≤42 days.a Do not refrigerate; do not store with needle in place.a Protect from direct heat and sunlight.a

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

For information on systemic interactions resulting from concomitant use, see Interactions.

Do not mix with any other insulin.1 6 7 17 18

Actions

  • Regulates glucose metabolism.a

  • Binds insulin receptors to lower blood glucose by increasing cellular uptake of glucose into skeletal muscle and fat; inhibits hepatic glucose production, lipolysis and proteolysis and increases protein synthesis.a

  • Longer duration of action and less intrapatient variability in blood glucose concentrations than with isophane insulin human.1 2 4 5 7 9 11

Advice to Patients

  • Provide copy of manufacturer’s patient information.1

  • Provide information regarding the potential risks and advantages of insulin detemir therapy.1

  • Importance of strict adherence to manufacturer’s instructions regarding use and proper storage of vials and injection devices (e.g., PenFill cartridges, FlexPen, InnoLet). a

  • Importance of providing instructions on safe disposal of needles.1 8

  • Provide instructions regarding self-monitoring of blood glucose concentrations.a c

  • Provide instructions regarding adherence to meal planning, regular physical exercise, periodic hemoglobin A1c (HbA1c) monitoring, and management of hypoglycemia and hyperglycemia.a

  • Importance of changing insulin dosage with caution and only under medical supervision. a c Discuss potential for alterations in insulin requirements in special situations (e.g., illness, concomitant agents that alter glycemic control, travel, emotional disturbances, other stresses).a Discuss potential for alterations in insulin requirements as a result of changes in physical activity, missed doses, or inadvertent administration of incorrect doses.a

  • Importance of administering insulin detemir either once daily with the evening meal or at bedtime; or twice daily, administered in the morning and after the evening meal, at bedtime, or 12 hours after the morning dose.1

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

  • Importance of informing clinicians of the development of skin reactions (redness, itching, or swelling) at injection site.a

  • Importance of informing clinicians of the development of generalized hypersensitivity reactions (trouble with shortness of breath, whole body rash, fast heartbeat, sweating).c

  • Inform patient that use of alcohol may increase risk of hypoglycemia.c

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.a c

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

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

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Insulin Detemir (Recombinant DNA Origin)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use

100 units/mL

Levemir (with m-cresol and phenol; available as FlexPen and Innolet prefilled syringes 3-mL PenFill cartridges and 10-mL vials)

Novo Nordisk

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Levemir 100UNIT/ML Solution (NOVO NORDISK): 10/$136.00 or 30/$378.82

Levemir FlexPen 100UNIT/ML Solution (NOVO NORDISK): 15/$242.99 or 45/$684.94

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 6, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Novo Nordisk. Levemir (insulin detemir) injection prescribing information. Princeton, NJ; 2005 Oct 19.

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 FlexPen: 4 steps for use. Princeton, NJ; 2006 Apr.

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.

a. Novo Nordisk. Levemir (insulin detemir [rDNA origin]) injection prescribing information. Princeton, NJ; 2007 May 16.

b. AHFS Drug Information 2008. McEvoy GK, ed. Insulins General Statement,. Bethesda, MD: American Society of Health-System Pharmacists; 2008:3196-3207.

c. Novo-Nordisk. Levemir (insulin detemir [rDNA origin]) important safety information. Princeton, NJ; undated. Available online. Accessed 2008 Apr 9.

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