Drug Monograph

Brand name:  Apidra

Generic name:  Insulin glulisine (rDNA origin)

Manufacturer:  Aventis Pharmaceuticals Inc.

Drug Class:  Rapid-acting insulin analog

Uses: 

            Labeled:  Indicated for the treatment of adult patients with type 1 or type 2 diabetes mellitus for control of hyperglycemia.^{1, 2}

Mechanism of Action:  Regulation of glucose metabolism.¹

Pharmacokinetics:

          Metabolism:  Based on animal studies, metabolism is similar to regular human insulin.  Insulin is metabolized rapidly, mostly in the liver but also in the kidneys and muscle tissues.  If metabolized in the kidneys, it is reabsorbed in the proximal tubules and returned to either the venous blood or metabolized, with only a small amount excreted unchanged in the urine.⁴ 

            Elimination:  It is comparable to regular human insulin in which only a small amount is excreted unchanged in the urine.⁴ It is unknown whether it is excreted in breast milk.²

Efficacy: ⁵ 

            Pivotal Study in Type 1 Diabetes Mellitus (Study 3001). Data on File. Aventis Pharmaceuticals. Accessed 6/2004.

                        This study was a randomized, multinational, multicenter, open-label, parallel, active control (lispro) compared to glulisine, both given with basal insulin Lantus.

                        The study was performed to determine the clinical efficacy and safety of glulisine in adult patients with type 1 diabetes.  A decrease in HbA1c without an increase in the Lantus dose was observed in the glulisine group.  The mean rate per month of symptomatic hypoglycemia was similar for both glulisine and lispro. 

                        A couple statistically significant differences between the two treatment groups could possibly affect the results.  The patients in the glulisine group had a mean diagnosis that was approximately two years longer than the lispro group and the mean duration of previous insulin treatment was also two years longer for glulisine.  The study was also open label, which could lead to bias. 

                        In conclusion, glulisine appears safe and effective for use in type 1 diabetes mellitus.

            Pivotal Study in Type 2 Diabetes Mellitus (Study 3002). Data on File. Aventis Pharmaceuticals. Accessed 6/2004.

                        This study was a multinational, multicenter, controlled, randomized, stratified, open-label, parallel-group, active control (regular insulin) compared to glulisine, both given with long-acting NPH. 

                        The study was performed to determine the safety and efficacy of glulisine in patients with type 2 diabetes.  By the end of the study, the glulisine group showed a statistically significant HbA1c decrease compared to the regular insulin group.  The incidence and mean rate per month of symptomatic hypoglycemia was similar for both agents. 

                        This study also had statistically significant differences between treatment groups that could possibly affect the results.  In the glulisine group, the patients were older and had been diagnosed with diabetes 1.3 years longer than the regular insulin group.  Glulisine is a rapid –acting insulin analog and regular insulin is short acting, so it might have been more efficacious to compare glulisine to lispro or aspart, both rapid-acting insulin analogs.                                               

                        In conclusion, glulisine appears clinically safe and effective in patients with type 2 diabetes when compared to regular insulin. 

            CSII in Patients with Type 1 Diabetes Mellitus (Study 3006). Data on File. Aventis Pharmaceuticals. Accessed 6/2004.

                        This study was a multicenter, randomized, parallel-group, controlled, open-label, active control (aspart) compared to glulisine.

                        The study was performed to determine the compatibility and safety of glulisine when administered by continuous subcutaneous insulin infusion (CSII) in patients with type 1 diabetes.  More patients in the glulisine group experienced hypoglycemia, however, the number of hypoglycemic episodes was higher before the start of treatment in the glulisine treated patients. 

                        All study participants were Caucasian, which could limit the ability to apply the data to all ethnic backgrounds.  The study was open-label which could lead to bias.

                        In conclusion, glulisine appears safe and compatible for use in a pump when given as an immediate bolus before meals, and continuously as basal insulin.

Adverse effects: 

            Hypoglycemia: ¹ The most common adverse effect with glulisine.²

            Local Allergy:  May experience redness, swelling, or itching at the site of injection.  These reactions usually resolve in a few days to weeks.  Lipodystrophy could occur at the site of injection and delay absorption of glulisine.¹

            Systemic Allergy:  Less common than a local reaction but could be more serious.  It may cause a rash over the entire body, cause shortness of breath, wheezing, decreased blood pressure, fast pulse, or sweating.  Severe cases could be life threatening.¹ 

Drug Interactions: ¹ 

            The following may reduce blood-glucose-lowering effect of glulisine:  corticosteroids, danazol, diazoxide, diuretics, sympathomimetic agents (eg: epinephrine, albuterol, terbutaline), glucagons, isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (eg: in oral contraceptives), protease inhibitors, and atypical antipsychotic medications (eg: olanzepine and clozapine).  

            The following may increase the blood-glucose-lowering effect and risk of hypoglycemia:  oral antidiabetic agents, ACE inhibitors, disopyramide, fibrates, fluoxetine, MAO inhibitors, pentoxifylline, propoxyphene, salicylates, and sulfonamide antibiotics.

            The following may either potentiate or weaken the blood-glucose-lowering effect of glulisine:  beta-blockers, clonidine, lithium salts, and alcohol.

            The following may reduce or mask the signs of hypoglycemia:  beta-blockers, clonidine, guanethidine, and reserpine. 

Dosing/Administration:

            Usual dose:  Should be individualized based on the health care professional’s advice.¹ In phase II/III studies, single doses of 0.1 and 0.3 units/kg were administered.² Glulisine is normally given with a longer-acting insulin or basal insulin analog.  It should be given within 15 minutes before a meal or within 20 minutes after starting a meal.  Glulisine should be given subcutaneous or used in an external infusion pump.  It can be mixed with NPH insulin when given subcutaneous but not via a pump.¹  

            Geriatric:  No specific difference from the adult dose.

            Pediatric:  Not been established.¹

            Renal impairment:  Dose adjustments may be necessary.¹

            Hepatic impairment:  Dose adjustments may be necessary.¹

Conclusion: 

Glulisine has been found safe and effective in patients with type 1 and type 2 diabetes mellitus along with being compatible for use in CSII.  When the regimen for glulisine is a SC bolus dose, the regimen should also include long-acting or basal insulin.  It acts like lispro or aspart in that it is a rapid-acting insulin analog with a shorter duration than regular human insulin.  Glulisine may be an alternative to the other rapid-acting insulin analogs in patients with Type 1 or Type 2 diabetes mellitus.

Recommended References:

1.      Apidra Product Labeling. Aventis Pharmaceuticals. Rev April 2004.

2.      DRUGDEXâ Editorial Staff- Insulin Glulisine, ln: Klasco RK (Ed): DRUGDEXâ System. Thomson MICROMEDEX, Greenwood Village, Colorado (Edition expires [6/2004]).

3.      DRUGDEXâ Editorial Staff- Insulin Lispro, ln: Klasco RK (Ed): DRUGDEXâ System. Thomson MICROMEDEX, Greenwood Village, Colorado (Edition expires [6/2004]).

4.      Sweetman S (Ed), Martindale: The Complete Drug Reference. London: Pharmaceutical Press. Electronic version, Thomson             MICROMEDEX, Greenwood Village, Colorado, (Edition expires [6/2004]).  

5.      Data on File. Aventis Pharmaceuticals. Accessed 6/2004.

Pam Spohn, PharmD student