Prior Authorization Guideline Guideline: PC - Apidra, Levemir Therapeutic Class: Hormones and Synthetic Substitutes Therapeutic Sub-Class: Antidiabetic Agents Client: CA, CO, NV, OK, OR, WA and AZ Approval Date: 8/2/2004 Revision Date: 6/6/2006 I. BENEFIT COVERAGE Table 1. Formulary status Non-Formulary Products Apidra (insulin glulisine) Levemir (insulin detemir) Formulary Products Humulin (human insulin, all products) Humulin 70/30, 50/50 (human insulin regular & isophane) Velosulin BR (human regular insulin buffered) Novolin (human insulin, all products) Novolin 70/30 (human regular insulin & isophane) Humalog (insulin lispro) Humalog Mix 75/25 (Insulin NPL/lispro) Humalog Mix 50/50 (insulin NPL/ lispro) Novolog (insulin aspart) NovoLog Mix 70/30 (insulin aspart protamine /insulin aspart) Lantus Vials (Insulin Glargine) ** For consideration of pen delivery systems (products available in a cartridge or penfill/devices), please refer to the antidiabetic agent delivery systems guideline** II. INDICATIONS A. FDA Approved Indications 1,2 1. Diabetes Mellitus
Apidra is indicated for the treatment of adult patients with diabetes mellitus for the control of hyperglycemia. Apidra has a more rapid onset of action and shorter duration of action than regular human insulin. Apidra should normally be used in regimens that include longer-acting insulin or basal insulin analog. Apidra may also be infused subcutaneously by external insulin infusion pumps. Levemir is indicated for once or twice-daily subcutaneous administration in the treatment of adult patients with diabetes mellitus who require basal (long acting) insulin for the control of hyperglycemia. III. GUIDELINE A. Apidra will be approved based on the following criterion: 1. Documented history of failure or intolerance to Humalog and Novolog. B. Levemir will be approved based on the following criterion: 1. Documented history of failure or intolerance to Lantus IV. CONTRAINDICATIONS AND WARNINGS A. Contraindications 1,2 Apidra is contraindicated during episodes of hypoglycemia and in patients hypersensitive to Apidra or any of its excipients. Levemir is contraindicated in patients hypersensitive to insulin detemir or any of its excipients. B. Warnings 1,2 1. Hypoglycemia Hypoglycemia is the most common adverse effect of insulin therapy. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. 2. Choice of Insulin Products Any change of insulin dose should be made cautiously and only under medical supervision. Changes in insulin strength, timing of dosing, manufacturer, type (e.g., regular, NPH, insulin analogs) may result in the need for a change in dosage. Concomitant oral anti-diabetic treatment may need to be adjusted. Because of the short duration of action of Apidra, patients with diabetes also require a longer-acting insulin or insulin infusion pump therapy to maintain adequate glucose control. V. DOSING 1,2 Apidra Apidra should be given within 15 minutes before a meal or within 20 minutes after starting a meal. Apidra is intended for subcutaneous
administration and for use by external infusion pump. The dosage of Apidra should be individualized and determined based on the physician s advice in accordance with the needs of the patient. Apidra should normally be used in regimens that include a longer-acting insulin or basal insulin analog. Levemir Levemir can be administered once- or twice-daily. The dose of Levemir should be adjusted according to blood glucose measurements. The dosage of Levemir should be individualized For patients with type 1 or type 2 diabetes on basal-bolus treatment, changing the basal insulin to Levemir can be done on a unit-to-unit basis. The dose of Levemir should then be adjusted to achieve glycemic targets. For insulin-naive patients with type 2 diabetes who are inadequately controlled on oral antidiabetic drugs, Levemir should be started at a dose of 0.1 to 0.2 U/kg once-daily in the evening or 10 units once- or twicedaily, and the dose adjusted to achieve glycemic targets. VI. AVAILABILITY 1,2 Levemir (100 Units of insulin detemir per ml [U-100]) is available in the following package sizes: 10 ml vial, 3 ml PenFill cartridges, 3 ml InnoLet, and 3 ml FlexPen Apidra 100 units per ml (U-100) is available in the following package size: 10 ml vials and 3 ml cartridge system*, in packages of 5 * Cartridge systems are for use only in OptiClik (Insulin Delivery Device) VII. BACKGROUND A. Description Apidra is a human insulin analogue that has a rapid onset of action and is short acting. It can be given just before or after meals for the treatment of diabetes. It is similar to insulin aspart and lispro. Levemir is a long-acting insulin analogue for the treatment of diabetes. Levemir has a fatty acid side chain that binds to tissue albumin at the subcutaneous injection site, resulting in prolonged activity. 3 It does not improve glycemic control or reduce overall hypoglycemic events in most trials that compared it to NPH insulin. It may be advantageous for those who experience nocturnal hypoglycemia or weight gain with NPH insulin. B. Clinical Studies 1. Diabetes Mellitus a. Levemir The efficacy and safety of Levemir given once-daily at bedtime or twice-daily was compared to that of once-daily or twice-daily NPH human insulin or once-daily insulin glargine in non-blinded, randomized, parallel studies of 6004 patients with diabetes. 2 In
general, patients treated with Levemir achieved levels of glycemic control similar to those treated with NPH or glargine, as measured by A1C. Vague et al. enrolled 448 patients with type 1 diabetes in an open parallel-group, comparative, six-month trial. 4 Patients were randomized in a 2:1 ratio to detemir or NPH before breakfast and bedtime; and insulin aspart before each meal. After six months, there were no significant differences in A1C levels at end point, between the detemir and NPH groups (7.60% and 7.64%, respectively). Fasting plasma glucose (FPG) levels were also similar in both groups at six months. Fluctuations in plasma glucose were lower in the detemir group compared with the NPH group (p <0.001). Patients receiving detemir had a mean weight loss of 0.6 kg, while patients receiving NPH had a mean weight increase of 0.6 kg at six months (p <0.001). Insulin detemir use was associated with a 22% relative risk reduction of all hypoglycemic events per subject month compared with NPH. Home et al. conducted an open-label 16-week trial involving 408 patients with type 1 diabetes. 5 Patients were randomized into three groups; insulin detemir before breakfast and at bedtime; insulin detemir every 12 hours; or NPH before breakfast and at bedtime. Mean A1C decreased by 0.82% in the insulin detemir before breakfast and at bedtime group, 0.85% in the insulin detemir every 12 hours group and 0.65% in the NPH group. There were no significant differences among all three groups. Russell-Jones et al. conducted a 6-month, randomized, open-label, controlled trial to compare the effects of QD detemir versus NPH in combination with regular human insulin (RHI) in patients with type 1 diabetes (n = 749). 6 After 6 months, FPG was lower with detemir than with NPH (-1.16 mmol/l difference; p = 0.001), whereas A1C did not differ between treatments (-0.12% [95% CI, -0.25 to 0.02]; p = NS). Day-to-day variability in self-measured fasting blood glucose was lower with detemir (SD, 2.82 vs. 3.60 mmol/l; p < 0.001). There was a 26% reduction in the relative risk of nocturnal hypoglycemia with detemir compared with NPH (p = 0.003). Gain in body weight was lower after 6 months with detemir than with NPH (-0.54 kg difference; p = 0.024). Hermansen et al. compared detemir, in combination with aspart to NPH insulin in combination with mealtime RHI in a 18-week, randomized, open-labeled, parallel trial of 595 patients with type 1 diabetes. 7 Glycemic control with detemir/aspart was improved in comparison with NPH /RHI (A1C: 7.88% vs. 8.11%; mean difference: -0.22%. [95% CI: -0.34 to -0.10]; p <0.001). Risk of overall and nocturnal hypoglycemia (23.00-06.00 hours) was, respectively, 21% (p = 0.036) and 55% (p <0.001) lower in the detemir/ aspart group than in the NPH /RHI group. Body weight was 1 kg lower with detemir/ aspart than with NPH /RHI (p <0.001). b. Apidra The safety and efficacy of Apidra was studied in adult patients with type 1 and type 2 diabetes (n =1833). 1 In a head to head comparison with insulin lispro in patients with type 1 diabetes, glycemic control and the rates of hypoglycemia requiring intervention from a third party were comparable for the two treatment regimens. Similar results were observed in patients with type 2 diabetes when Apidra and RHI were compared to each other on a background on basal insulin NPH therapy. Apidra was shown to be noninferior to either lispro or RHI in terms of change in A1C from baseline to endpoint and blood glucose values. Dailey et al. conducted a randomized, open-label, parallel-group study in 876 relatively well-controlled patients with type 2 diabetes (mean A1C 7.55%). 8 Patients were treated with glulisine/nph or RHI/NPH for up to 26 weeks. Subjects were allowed to continue
the same dose of prestudy regimens of oral antidiabetic agent therapy unless hypoglycemia necessitated a dose change. A slightly greater reduction from baseline to end point of A1C was seen in the glulisine group versus RHI ( 0.46 vs. 0.30% with RHI; p = 0.0029). The clinical significance of these differences is yet to be established. Symptomatic hypoglycemia (overall, nocturnal, and severe) and weight gain were comparable between the two treatment groups. Dreyer et al. conducted a randomized, controlled, open-label, study to compare glulisine to lispro in adults patients with type 1 diabetes (n = 683). 9 Over the 26-week study, a similar reduction in mean A1C occurred in both groups (adjusted mean change from baseline -0.14% in both groups). There was no relevant difference between the two groups in the reporting of symptomatic hypoglycemia (overall, nocturnal and severe). C. National Guidelines 1. American Diabetes Association (2005) 10 Aggressive glycemic management with insulin may reduce morbidity in patients with severe acute illness, preoperatively, following myocardial infarction, and in pregnancy. 2. Canadian Diabetes Association (2003) 11 The current treatment of type 1 diabetes involves insulin products that are classified by duration of effect. They include rapid-acting insulin aspart and lispro; short-acting regular insulin; intermediate-acting NPH insulin; and long-acting insulin glargine. The treatment of patients with type 2 diabetes may include a combination of lifestyle management and oral hypoglycemic agents. Multiple oral hypoglycemic agents or insulin in combination with oral hypoglycemic agents may be used if treatment goals are not reached. Insulin monotherapy is generally used when diet, exercise, lifestyle and oral hypoglycemic agents are ineffective or contraindicated. It may be used as initial therapy in the presence of marked hyperglycemia (A1C >9.0%). IX. REFERENCES 1. Apidra Prescribing Information, Sanofi Aventis. December 2005. 2. Levemir Prescribing Information, Novo Nordisk. June 2005. 3. Canadian Coordinating Office For Health Technology Assessment. Insulin Detemir for Diabetes Mellitus. No. 59 July 2004. Available at: http://www.cadth.ca/media/pdf/108_no59_insulin_detemir_edrug_e.pdf. Accessed April 21, 2006. 4. Vague P, Selam JL, Skeie S, De L, I, Elte JW, Haahr H, et al. Insulin detemir is associated with more predictable glycemic control and reduced risk of hypoglycemia than NPH insulin in patients with type 1 diabetes on a basal-bolus regimen with premeal insulin aspart. Diabetes Care 2003; 26(3): 590-6. 5. Home P, Bartley P, Russell-Jones D, Hanaire-Broutin H, Heeg JE, Abrams P, et al. Insulin detemir offers improved glycemic control compared with NPH insulin in people with type 1 diabetes: a randomized clinical trial. Diabetes Care 2004; 27(5): 1081-7. 6. Russell-Jones D, Simpson R, Hylleberg B, Draeger E, Bolinder J. Effects of QD insulin detemir or neutral protamine Hagedorn on blood glucose control in patients with type I diabetes mellitus using a basal-bolus regimen. Clin Ther. 2004;26(5):724-36. 7. Hermansen K, Fontaine P, Kukolja KK, Peterkova V, Leth G, Gall MA. Insulin analogues (insulin detemir and insulin aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basal-bolus therapy for patients with type 1 diabetes. Diabetologia. 2004; 47(4): 622-9.
8. Dailey G, Rosenstock J, Moses RG, Ways K. Insulin Glulisine Provides Improved Glycemic Control in Patients With Type 2 Diabetes. Diabetes Care 2004 (27): 2363-2368. 9. Dreyer M, Prager R, Robinson A, et al. Efficacy and safety of insulin glulisine in patients with type 1 diabetes. Horm Metab Res. 2005;37(11):702-7. 10. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2005;28 (suppl 1):S8-14. 11. Canadian Diabetes Association. Pharmacologic management of type 2 diabetes. In: 2003 Clinical practice guidelines for the prevention and management of diabetes in Canada. Toronto: The Association; 2003. Available: http://www.diabetes.ca/cpg2003/chapters.aspx Accessed April 21, 2006. This Prior Authorization Guideline represents the recommendation of Prescription Solutions Pharmacy and Therapeutics (P&T) Committee. It is based upon the P&T Committee s review of the available evidence as of the date of drafting or revision of this Prior Authorization Guideline. It is subject to updating from time to time, based upon changes in scientific knowledge and information. This Prior Authorization Guideline is intended as a resource for making coverage decisions for Health Plan members, but it does not replace an individualized case-by-case review and medical necessity determination for each Health Plan member. Copyright 2006 by Prescription Solutions. All rights reserved. This Prior Authorization Guideline is intended for use by Prescription Solutions and Health Plan employees and applicable contracted providers and practitioners only. The information contained in this Prior Authorization Guideline is confidential and proprietary to Prescription Solutions and shall not be used, reproduced, or transferred in whole or in part without Prescription Solutions prior written consent.