Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 15 May 2018

Indication(s)

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)

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Advisory information

contraindications

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)

Adverse reactions

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 <36 mg/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)].

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION The dosage of APIDRA must be individualized (2.1) 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) 2.1 Dosage considerations APIDRA is a recombinant insulin analog that is equipotent to human insulin (i.e. one unit of APIDRA has the same glucose-lowering effect as one unit of regular human insulin) when given intravenously.

When given subcutaneously, APIDRA has a more rapid onset of action and a shorter duration of action than regular human insulin.

The dosage of

APIDRA must be individualized.

Blood glucose monitoring is essential in all patients receiving insulin therapy.

The total daily insulin requirement may vary and is usually between 0.5 to 1 Unit/ kg/day.

Insulin requirements may be altered during stress, major illness, or with changes in exercise, meal patterns, or coadministered drugs.

2.2 Subcutaneous administration APIDRA should be given within 15 minutes before a meal or within 20 minutes after starting a meal.

APIDRA given by subcutaneous injection should generally be used in regimens with an intermediate or long-acting insulin.

APIDRA should be administered by subcutaneous injection in the abdominal wall, thigh, or upper arm.

Injection sites should be rotated within the same region (abdomen, thigh or upper arm) from one injection to the next to reduce the risk of lipodystrophy [See Adverse Reactions (6.1)].

2.3 Continuous subcutaneous infusion (insulin pump) APIDRA may be administered by continuous subcutaneous infusion in the abdominal wall.

Do not use diluted or mixed insulins in external insulin pumps.

Infusion sites should be rotated within the same region to reduce the risk of lipodystrophy [See Adverse Reactions (6.1)].

The initial programming of the external insulin infusion pump should be based on the total daily insulin dose of the previous regimen.

The following insulin pumps have been used in APIDRA clinical trials conducted by sanofi-aventis, the manufacturer of APIDRA: Disetronic® H-Tron® plus V100 and D-Tron® with Disetronic catheters (Rapid™, Rapid C™, Rapid D™, and Tender™) MiniMed® Models 506, 507, 507c and 508 with MiniMed catheters (Sof-set Ultimate QR™, and Quick-set™).

Before using a different insulin pump with APIDRA, read the pump label to make sure the pump has been evaluated with APIDRA. Physicians and patients should carefully evaluate information on pump use in the APIDRA prescribing information, Patient Information Leaflet, and the pump manufacturer 's manual.

APIDRA-specific information should be followed for in-use time, frequency of changing infusion sets, or other details specific to APIDRA usage, because APIDRA-specific information may differ from general pump manual instructions.

Failure to follow APIDRA-specific instructions may lead to serious adverse events.

Patients administering APIDRA by continuous subcutaneous infusion must have an alternative insulin delivery system in case of pump system failure.

Based on in_vitro studies which have shown loss of the preservative, metacresol and insulin degradation, APIDRA in the reservoir should be changed at least every 48 hours.

APIDRA should not be exposed to temperatures greater than 98.6°F (37°C).

In clinical use, the infusion sets and the APIDRA in the reservoir must be changed at least every 48 hours [See Warnings and Precautions (5.8) and How Supplied/Storage and Handling (16.2)].

2.4 Intravenous administration APIDRA can be administered intravenously under medical supervision for glycemic control with close monitoring of blood glucose and serum potassium to avoid hypoglycemia and hypokalemia.

For intravenous use, APIDRA should be used at concentrations of 0.05 Units/mL to 1 Unit/mL insulin glulisine in infusion systems using polyvinyl chloride (PVC) bags.

APIDRA has been shown to be stable only in normal saline solution (0.9 % sodium chloride).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Do not administer insulin mixtures intravenously.

Use in special populations

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.

Pregnancy and lactation
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.

Interactions

5.10 Drug interactions Some medications may alter insulin requirements and the risk for hypoglycemia or hyperglycemia [See Drug Interactions (7)].

More information

Category Value
Authorisation number NDA021629
Agency product number 7XIY785AZD
Orphan designation No
Product NDC 0088-2502,0088-2500
Date Last Revised 19-03-2015
Type HUMAN PRESCRIPTION DRUG
RXCUI 485210
Storage and handling

16.2 Storage Do not use after the expiration date (see carton and container).

Unopened Vial/SoloStar Unopened APIDRA vials and SoloStar should be stored in a refrigerator, 36°F-46°F (2°C-8°C).

Protect from light.

APIDRA should not be stored in the freezer and it should not be allowed to freeze.

Discard if it has been frozen.

Unopened vials/SoloStar not stored in a refrigerator must be used within 28 days.

Open (In-Use) Vial: Opened vials, whether or not refrigerated, must be used within 28 days.

If refrigeration is not possible, the open vial in use can be kept unrefrigerated for up to 28 days away from direct heat and light, as long as the temperature is not greater than 77°F (25°C).

Open (In-Use) SoloStar prefilled pen: The opened (in-use) SoloStar should NOT be refrigerated but should be kept below 77°F (25°C) away from direct heat and light.

The opened (in-use) SoloStar kept at room temperature must be discarded after 28 days.

Infusion sets:

Infusion sets (reservoirs, tubing, and catheters) and the APIDRA in the reservoir must be discarded after 48 hours of use or after exposure to temperatures that exceed 98.6°F (37°C).

Intravenous use: Infusion bags prepared as indicated under DOSAGE AND ADMINISTRATION (2.4) are stable at room temperature for 48 hours.

Marketing authorisation holder Sanofi-Aventis U.S. LLC