|Warnings and Precautions (5.1) ||02/2015 |
|Warnings and Precautions (5.11) ||02/2014 |
1 INDICATIONS AND USAGE APIDRA is indicated to improve glycemic control in adults and children with diabetes mellitus. APIDRA is a rapid acting human insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus. (1)
| Subcutaneous Injection ||Administer within 15 minutes before a meal or within 20 minutes after starting a meal. Use in a regimen with an intermediate or long-acting insulin. (2.1, 2.2) |
| Continuous Subcutaneous Infusion Pump ||APIDRA must not be mixed or diluted when used in an external insulin infusion pump. (2.3) |
| Intravenous Infusion ||Infuse intravenously (0.05 Units/mL to 1 Units/mL APIDRA in 0.9% sodium chloride using polyvinyl chloride infusion bags) only under strict medical supervision with close monitoring of blood glucose and potassium. (2.4) |
3 DOSAGE FORMS AND STRENGTHS APIDRA 100 units per mL (U-100) is available as: 10 mL vials 3 mL SoloStar prefilled pen APIDRA 100 units/mL (U-100) is available as: (3) 10 mL vials 3 mL SoloStar® prefilled pen
4 CONTRAINDICATIONS APIDRA is contraindicated: during episodes of hypoglycemia in patients who are hypersensitive to APIDRA or to any of its excipients When used in patients with known hypersensitivity to APIDRA or its excipients, patients may develop localized or generalized hypersensitivity reactions [See Adverse Reactions (6.1)]. Do not use during episodes of hypoglycemia (4) Do not use in patients with hypersensitivity to APIDRA or any of its excipients (4)
5 WARNINGS AND PRECAUTIONS Never share an APIDRA SoloStar pen between patients, even if the needle is changed (5.1) Do not reuse or share needles or syringes between patients (5.1) Dose adjustment and monitoring: Closely monitor blood glucose in all patients treated with insulin. Change insulin regimens cautiously and only under medical supervision.(5.2) Hypoglycemia: Most common adverse reaction of insulin therapy and may be life-threatening (5.3) Allergic reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with any insulin, including APIDRA (5.4) Hypokalemia: All insulins, including APIDRA can cause hypokalemia, which if untreated, may result in respiratory paralysis, ventricular arrhythmia, and death (5.5) Renal or hepatic impairment: Like all insulins, may require a reduction in the APIDRA dose (5.6) Mixing: APIDRA for subcutaneous injection should not be mixed with insulins other than NPH insulin. Do not mix APIDRA with any insulin for intravenous administration or for use in a continuous infusion pump (5.7) Pump use: Change the APIDRA in the pump reservoir every 48 hours (5.8) Intravenous use: Frequently monitor for hypoglycemia and hypokalemia. (5.9) Fluid retention and heart failure can occur with concomitant use of thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation of TZD if heart failure occurs (5.11) 5.1 Never share an APIDRA SoloStar pen or syringe or needle between patients APIDRA SoloStar pens must never be shared between patients, even if the needle is changed. Patients using APIDRA vials must never reuse or share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens. 5.2 Dosage adjustment and monitoring Glucose monitoring is essential for patients receiving insulin therapy. Changes to an insulin regimen should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a change in insulin dose. Concomitant oral antidiabetic treatment may need to be adjusted. As with all insulin preparations, the time course of action for APIDRA may vary in different individuals or at different times in the same individual and is dependent on many conditions, including the site of injection, local blood supply, or local temperature. Patients who change their level of physical activity or meal plan may require adjustment of insulin dosages. 5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction of insulin therapy, including APIDRA. The risk of hypoglycemia increases with tighter glycemic control. Patients must be educated to recognize and manage hypoglycemia. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person and/or parenteral glucose infusion or glucagon administration has been observed in clinical trials with insulin, including trials with APIDRA. The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications may also alter the risk of hypoglycemia [See Drug Interactions (7)]. As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food intake). The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Rapid changes in serum glucose levels may induce symptoms similar to hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic nerve disease, use of medications such as beta-blockers [See Drug Interactions (7)], or intensified diabetes control. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient's awareness of hypoglycemia. Intravenously administered insulin has a more rapid onset of action than subcutaneously administered insulin, requiring closer monitoring for hypoglycemia. 5.4 Hypersensitivity and allergic reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including APIDRA [See Adverse reactions (6.1)]. 5.5 Hypokalemia All insulin products, including APIDRA, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations). Monitor glucose and potassium frequently when APIDRA is administered intravenously. 5.6 Renal or hepatic impairment Frequent glucose monitoring and insulin dose reduction may be required in patients with renal or hepatic impairment [See Clinical Pharmacology (12.4)]. 5.7 Mixing of insulins APIDRA for subcutaneous injection should not be mixed with insulin preparations other than NPH insulin. If APIDRA is mixed with NPH insulin, APIDRA should be drawn into the syringe first. Injection should occur immediately after mixing. Do not mix APIDRA with other insulins for intravenous administration or for use in a continuous subcutaneous infusion pump. APIDRA for intravenous administration should not be diluted with solutions other than 0.9% sodium chloride (normal saline). The efficacy and safety of mixing APIDRA with diluents or other insulins for use in external subcutaneous infusion pumps have not been established. 5.8 Subcutaneous insulin infusion pumps When used in an external insulin pump for subcutaneous infusion, APIDRA should not be diluted or mixed with any other insulin. APIDRA in the reservoir must be changed at least every 48 hours. APIDRA should not be exposed to temperatures greater than 98.6°F (37°C). Malfunction of the insulin pump or infusion set or handling errors or insulin degradation can rapidly lead to hyperglycemia, ketosis and diabetic ketoacidosis. Prompt identification and correction of the cause of hyperglycemia or ketosis or diabetic ketoacidosis is necessary. Interim subcutaneous injections with APIDRA may be required. Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available. [See Dosage and Administration (2.3), How Supplied/Storage and Handling (16), and Patient Counseling Information (17.3)]. 5.9 Intravenous administration When APIDRA is administered intravenously, glucose and potassium levels must be closely monitored to avoid potentially fatal hypoglycemia and hypokalemia. Do not mix APIDRA with other insulins for intravenous administration. APIDRA may be diluted only in normal saline solution. 5.10 Drug interactions Some medications may alter insulin requirements and the risk for hypoglycemia or hyperglycemia [See Drug Interactions (7)]. 5.11 Fluid retention and heart failure with concomitant use of PPAR-gamma agonists Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including APIDRA and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.
6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere: Hypoglycemia [See Warnings and Precautions (5.3)] Hypokalemia [See Warnings and Precautions (5.5)] Adverse reactions commonly associated with APIDRA include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, and rash. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical trial experience Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. The frequencies of adverse drug reactions during APIDRA clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below. Table 1: Treatment –emergent adverse events in pooled studies of adults with type 1 diabetes (adverse events with frequency ≥ 5%) APIDRA, % (n=950) All comparatorsInsulin lispro, regular human insulin, insulin aspart, % (n=641) Nasopharyngitis 10.6 12.9 HypoglycemiaOnly severe symptomatic hypoglycemia 6.8 6.7 Upper respiratory tract infection 6.6 5.6 Influenza 4.0 5.0 Table 2: Treatment –emergent adverse events in pooled studies of adults with type 2 diabetes (adverse events with frequency ≥ 5%) APIDRA, % (n=883) Regular human insulin, % (n=883) Upper respiratory tract infection 10.5 7.7 Nasopharyngitis 7.6 8.2 Edema peripheral 7.5 7.8 Influenza 6.2 4.2 Arthralgia 5.9 6.3 Hypertension 3.9 5.3 Pediatrics Table 3 summarizes the adverse reactions occurring with frequency higher than 5% in a clinical study in children and adolescents with type 1 diabetes treated with APIDRA (n=277) or insulin lispro (n=295). Table 3: Treatment –emergent adverse events in children and adolescents with type 1 diabetes (adverse reactions with frequency ≥ 5%) APIDRA, % (n=277) Lispro, % (n=295) Nasopharyngitis 9.0 9.5 Upper respiratory tract infection 8.3 10.8 Headache 6.9 11.2 Hypoglycemic seizure 6.1 4.7 Severe symptomatic hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including APIDRA [See Warnings and Precautions (5.2)]. The rates and incidence of severe symptomatic hypoglycemia, defined as hypoglycemia requiring intervention from a third party, were comparable for all treatment regimens (see Table 4). In the phase 3 clinical trial, children and adolescents with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to adults with type 1 diabetes. (see Table 4) [See Clinical Studies (14)]. Table 4: Severe Symptomatic HypoglycemiaSevere symptomatic hypoglycemia defined as a hypoglycemic event requiring the assistance of another person that met one of the following criteria: the event was associated with a whole blood referenced blood glucose <36mg/dL or the event was associated with prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration. Type 1 Diabetes Adults 12 weeks with insulin glargine Type 1 Diabetes Adults 26 weeks with insulin glargine Type 2 Diabetes Adults 26 weeks with NPH human insulin Type 1 Diabetes Pediatrics 26 weeks APIDRA Pre-meal APIDRA Post-meal Regular Human Insulin APIDRA Insulin Lispro APIDRA Regular Human Insulin APIDRA Insulin Lispro Events per month per patient 0.05 0.05 0.13 0.02 0.02 0.00 0.00 0.09 0.08 Percent of patients (n/total N) 8.4% (24/286) 8.4% (25/296) 10.1% (28/278) 4.8% (16/339) 4.0% (13/333) 1.4% (6/416) 1.2% (5/420) 16.2% (45/277) 19.3% (57/295) Insulin initiation and intensification of glucose control Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy. Lipodystrophy Long-term use of insulin, including APIDRA, can cause lipodystrophy at the site of repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection or infusion sites within the same region to reduce the risk of lipodystrophy. [See Dosage and Administration (2.2, 2.3)]. Weight gain Weight gain can occur with insulin therapy, including APIDRA, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Peripheral Edema Insulin, including APIDRA, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Adverse Reactions with Continuous Subcutaneous Insulin Infusion (CSII) In a 12-week randomized study in patients with type 1 diabetes (n=59), the rates of catheter occlusions and infusion site reactions were similar for APIDRA and insulin aspart treated patients (Table 5). Table 5: Catheter Occlusions and Infusion Site Reactions. APIDRA (n=29) insulin aspart (n=30) Catheter occlusions/month 0.08 0.15 Infusion site reactions 10.3% (3/29) 13.3% (4/30) Allergic Reactions Local Allergy As with any insulin therapy, patients taking APIDRA may experience redness, swelling, or itching at the site of injection. These minor reactions usually resolve in a few days to a few weeks, but in some occasions may require discontinuation of APIDRA. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Systemic Allergy Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin, including APIDRA. Generalized allergy to insulin may cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis. In controlled clinical trials up to 12 months duration, potential systemic allergic reactions were reported in 79 of 1833 patients (4.3%) who received APIDRA and 58 of 1524 patients (3.8%) who received the comparator short-acting insulins. During these trials treatment with APIDRA was permanently discontinued in 1 of 1833 patients due to a potential systemic allergic reaction. Localized reactions and generalized myalgias have been reported with the use of metacresol, which is an excipient of APIDRA. Antibody Production In a study in patients with type 1 diabetes (n=333), the concentrations of insulin antibodies that react with both human insulin and insulin glulisine (cross-reactive insulin antibodies) remained near baseline during the first 6 months of the study in the patients treated with APIDRA. A decrease in antibody concentration was observed during the following 6 months of the study. In a study in patients with type 2 diabetes (n=411), a similar increase in cross-reactive insulin antibody concentration was observed in the patients treated with APIDRA and in the patients treated with human insulin during the first 9 months of the study. Thereafter the concentration of antibodies decreased in the APIDRA patients and remained stable in the human insulin patients. There was no correlation between cross-reactive insulin antibody concentration and changes in HbA1c, insulin doses, or incidence of hypoglycemia. The clinical significance of these antibodies is not known. APIDRA did not elicit a significant antibody response in a study of children and adolescents with type 1 diabetes. 6.2 Postmarketing experience The following adverse reactions have been identified during post-approval use of APIDRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Medication errors have been reported in which other insulins, particularly long-acting insulins, have been accidentally administered instead of APIDRA [See Patient Counseling Information (17)] .
5.10 Drug interactions Some medications may alter insulin requirements and the risk for hypoglycemia or hyperglycemia [See Drug Interactions (7)].
8 USE IN SPECIFIC POPULATIONS APIDRA has not been studied in children under 4 years of age (8.4) 8.1 Pregnancy Pregnancy Category C: Reproduction and teratology studies have been performed with insulin glulisine in rats and rabbits using regular human insulin as a comparator. Insulin glulisine was given to female rats throughout pregnancy at subcutaneous doses up to 10 Units/kg once daily (dose resulting in an exposure 2 times the average human dose, based on body surface area comparison) and did not have any remarkable toxic effects on embryo-fetal development. Insulin glulisine was given to female rabbits throughout pregnancy at subcutaneous doses up to 1.5 Units/kg/day (dose resulting in an exposure 0.5 times the average human dose, based on body surface area comparison). Adverse effects on embryo-fetal development were only seen at maternal toxic dose levels inducing hypoglycemia. Increased incidence of post-implantation losses and skeletal defects were observed at a dose level of 1.5 Units/kg once daily (dose resulting in an exposure 0.5 times the average human dose, based on body surface area comparison) that also caused mortality in dams. A slight increased incidence of post-implantation losses was seen at the next lower dose level of 0.5 Units/kg once daily (dose resulting in an exposure 0.2 times the average human dose, based on body surface area comparison) which was also associated with severe hypoglycemia but there were no defects at that dose. No effects were observed in rabbits at a dose of 0.25 Units/kg once daily (dose resulting in an exposure 0.1 times the average human dose, based on body surface area comparison). The effects of insulin glulisine did not differ from those observed with subcutaneous regular human insulin at the same doses and were attributed to secondary effects of maternal hypoglycemia. There are no well-controlled clinical studies of the use of APIDRA in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is essential for patients with diabetes or a history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is essential in these patients. 8.3 Nursing mothers It is unknown whether insulin glulisine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when APIDRA is administered to a nursing woman. Use of APIDRA is compatible with breastfeeding, but women with diabetes who are lactating may require adjustments of their insulin doses. 8.4 Pediatric use The safety and effectiveness of subcutaneous injections of APIDRA have been established in pediatric patients (age 4 to 17 years) with type 1 diabetes [See Clinical Studies (14.4)]. APIDRA has not been studied in pediatric patients with type 1 diabetes younger than 4 years of age and in pediatric patients with type 2 diabetes. As in adults, the dosage of APIDRA must be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood glucose. 8.5 Geriatric use In clinical trials (n=2408), APIDRA was administered to 147 patients ≥65 years of age and 27 patients ≥75 years of age. The majority of this small subset of elderly patients had type 2 diabetes. The change in HbA1c values and hypoglycemia frequencies did not differ by age. Nevertheless, caution should be exercised when APIDRA is administered to geriatric patients.