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Risk first

Contraindications

4 CONTRAINDICATIONS APIDRA is contraindicated: during episodes of hypoglycemia in patients with known hypersensitivity to insulin glulisine or to any of the excipients in APIDRA
systemic allergic reactions have occurred with APIDRA [see Adverse Reactions (6.1) ] .
Do not use during episodes of hypoglycemia.
( 4 ) Do not use in patients with hypersensitivity to insulin glulisine or any excipients in APIDRA ( 4 )

Precautions

patients, even if the needle is changed.
( 5.1 ) Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen: Make changes to a patient's insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring.
( 5.2 ) Hypoglycemia: May be life-threatening.
Increase frequency of glucose monitoring with changes to: insulin dosage, coadministered glucose lowering medications, meal pattern, physical activity
and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness.
( 5.3 ) Hypoglycemia Due to Medication Errors: Accidental mix-ups between insulin products can occur.
Instruct patients to check insulin labels before injection.
( 5.4 ) Hypokalemia: May be life-threatening.
Monitor potassium levels in patients at risk for hypokalemia and treat if indicated.
( 5.5 ) Hypersensitivity Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur.
Discontinue APIDRA, monitor and treat if indicated.
( 5.6 ) Fluid Retention and Heart Failure Can Occur with Concomitant Use of Thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure

Point of care

Dosing

Adult

instructions. ( 2.1 , 2.2 ) Individualize and adjust the dosage of APIDRA based on route of administration, individual's metabolic needs, blood glucose monitoring results, and glycemic control goal. ( 2.3 ) Dosage adjustments may be needed when switching from another insulin, with changes in physical activity, changes in concomitant medications, changes in meal patterns, changes in renal or hepatic function or during acute illness. ( 2.3 ) Subcutaneous Injection: ( 2.2 ) Inject within 15 minutes before a meal or within 20 minutes after starting a meal into the abdomen, thigh, or upper arm. Rotate injection sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Should generally be used in regimens with an intermediate or long-acting insulin. Continuous Subcutaneous Infusion (Insulin Pump): ( 2.2 ) Refer to the insulin infusion pump user manual to see if APIDRA can be used. Use in accordance with the insulin pump instructions for use. Administer by continuous subcutaneous infusion using an insulin pump in a region recommended in the instructions from the pump manufacturer. Rotate infusion sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not mix with other insulins or diluents in the pump. Intravenous Administration: Administer only under medical supervision after diluting to concentrations from 0.05 to 1 unit/mL APIDRA in 0.9% sodium chloride injection, USP using polyvinyl chloride infusion bags. ( 2.2 ) 2.1 Important Administration Instructions Always check insulin label before administration [see Warnings and Precautions (5.4) ] . Inspect visually for particulate matter and discoloration. Only use APIDRA if the solution appears clear and colorless. Use APIDRA SoloStar prefilled pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose. 2.2 Route of Administration Instructions Subcutaneous Injection Inject APIDRA subcutaneously within 15 minutes before a meal or within 20 minutes after starting a meal into the abdominal wall, thigh, or upper arm. Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2) , Adverse Reactions (6) ] . APIDRA given by subcutaneous injection should generally be used in regimens with an intermediate or long-acting insulin. The APIDRA SoloStar prefilled pen dials in 1-unit increments. Do not mix APIDRA for subcutaneous injection with insulins other than NPH insulin. If APIDRA is mixed with NPH insulin, draw APIDRA into the syringe first and inject immediately after mixing. Continuous Subcutaneous Infusion (Insulin Pump) Refer to the continuous subcutaneous insulin infusion pump user manual to see if APIDRA can be used with the insulin pump. Use APIDRA in accordance with the insulin pump system's instructions for use. Administer APIDRA by continuous subcutaneous infusion in a region recommended in the instructions from the pump manufacturer. Rotate infusion sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. [see Warnings and Precautions (5.2) , Adverse Reactions (6) ] . Train patients using continuous subcutaneous insulin infusion pump therapy to administer insulin by injection and have alternate insulin therapy available in case of insulin pump failure [see Warnings and Precautions (5.8) ] . During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2) ] . Change APIDRA in the reservoir at least every 48 hours or according to the pump user manual, whichever is shorter. Change the infusion sets and the infusion set insertion site according to the manufacturer's user manual. Do not dilute or mix APIDRA when administering by continuous subcutaneous infusion. Do not expose APIDRA in the pump reservoir to temperatures greater than 98.6°F (37°C). Intravenous Administration Administer APIDRA intravenously only under medical supervision with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia [see Warnings and Precautions (5.3 , 5.5) ] . Dilute APIDRA to concentrations from 0.05 unit/mL to 1 unit/mL insulin glulisine in infusion systems using polyvinyl chloride (PVC) infusion bags. Diluted APIDRA is stable at room temperature for 48 hours only in normal saline solution (0.9% Sodium Chloride Injection, USP) [see How Supplied/Storage and Handling (16.2) ] . APIDRA is not compatible with Dextrose solution and Ringers solution. 2.3 Dosage Information Individualize and adjust the dosage of APIDRA based on the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal. Dose adjustments may be needed when switching from another insulin, with changes in physical activity, changes in concomitant medications, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function, or during acute illness to minimize the risk of hypoglycemia or hyperglycemia [see Warnings and Precautions (5.2 , 5.3) , Drug Interactions (7) , Use in Specific Populations (8.6 , 8.7) ].

Paediatric

8.4 Pediatric Use The safety and effectiveness of APIDRA to improve glycemic control have been established in pediatric patients. Use of APIDRA for this indication is supported by evidence from an active-controlled non-inferiority study in pediatric patients 4 years of age and older with type 1 diabetes mellitus treated with APIDRA (n=271) and from studies in adults with diabetes mellitus [see Clinical Pharmacology (12.3) , and Clinical Studies (14) ] . In the clinical trials, pediatric patients with type 1 diabetes mellitus had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to adults with type 1 diabetes mellitus [see Adverse Reactions (6.1) ] .

Renal

Reduced insulin clearance — lower doses often needed in advanced CKD.

CrCl 0–120: Confirm renal dosing in product SmPC / primary label.

Hepatic

Impaired gluconeogenesis increases hypo risk.

Safety

Drug interactions

Open checker →

///// It differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid.
Due to increased charge repulsion there is less likelihood of formation of hexamers hence create faster-acting insulin.

Safety

Adverse effects

elsewhere: Hypoglycemia [see Warnings and Precautions (5.3) ] Hypoglycemia Due to Medication Errors [see Warnings and Precautions (5.4) ] Hypokalemia [see Warnings and Precautions (5.5) ] Hypersensitivity Reactions [see Warnings and Precautions (5.6) ] Adverse reactions commonly associated with APIDRA include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, and weight gain.
( 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 Trials 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 data in Table 1 reflect the exposure of 1591 patients with type 1 diabetes to APIDRA or comparators [see Clinical Studies (14.1) ] .
The type 1 diabetes population had the following characteristics: Mean age was 39.74 years. 54.5 % were male, 95.5% were Caucasian, 1.5% were Black or African American.
The data in Table 2 reflect the exposure of 1766 patients with type 2 diabetes to APIDRA or comparators [see Clinical Studies (14.2) ] .
The type 2 diabetes population had the following characteristics: Mean age was 59.08 years. 51.2% were male, 88.5% were Caucasian, 7.2% were Black or African American.
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: Adverse Reactions Occurring ≥5% in Pooled Studies of Adults with Type 1 Diabetes APIDRA, % (n=950) All Comparators Insulin lispro, regular human insulin, insulin aspart , % (n=641) Nasopharyngitis 10.6 12.9 Hypoglycemia Only severe symptomatic hypoglycemia 6.8 6.7 Upper respiratory tract infection 6.6 5.6 Influenza 4.0 5.0 Table 2: Adverse Reactions Occurring ≥5% in Pooled Studies of Adults with Type 2 Diabetes 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 pediatric patients with type 1 diabetes treated with APIDRA (n=277) or insulin lispro (n=295).
Table 3: Adverse Reactions Occurring ≥5% in Pediatric Patients with Type 1 Diabetes APIDRA, % (n=277) Insulin 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 was the most commonly observed adverse reaction in patients treated with insulin, including APIDRA.
The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors.
For these reasons, comparing rates of hypoglycemia in clinical trials for APIDRA with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that occur in clinical practice.
The rates and incidence of severe symptomatic hypoglycemia, defined as hypoglycemia requiring intervention from a third party are presented in Table 4.
In the clinical trials, 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 Hypoglycemia Severe 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.

Use

Indications

Indications to the use of insulin
Diabetes mellitus
diabetes keto-acidosis
gestational diabetes mellitus
malnutrition-related diabetes mellitus
diagnosis of growth hormone deficiency.
Clinical selection for Insulin Glulisine should follow culture results where relevant, Kenya STG/EML recommendations, and the current product SmPC.
Class context: Insulin Analog [EPC].
Confirm site-specific dose, duration and monitoring before prescribing.

Pharmacology

Mode of action

Insulin: controls the storage and metabolism of carbohydrates, proteins, and fats.

Insulin: → controls the storage and metabolism of car… → This occurs primarily in the liver, in mus…

Full mechanism text

Insulin: controls the storage and metabolism of carbohydrates, proteins, and fats. This occurs primarily in the liver, in muscle, and in adipose tissues after it binding to receptor sites on cellular plasma membranes. is known to affect cell membrane transport characteristics, cellular growth, enzyme activation and inhibition, and changes in protein and fat metabolism. promotes uptake of carbohydrates, proteins, and fats in most tissues. stimulates protein and free fatty acid synthesis. It inhibits the release of free fatty acid from adipose cells. increases active glucose transport through muscle and adipose cellular membranes promotes the conversion of intracellular glucose to glycogen and free fatty acid to triglyceride [storage forms] increases hepatic glucose conversion to glycogen and suppresses hepatic glucose output. stimulates growth hormone re secretion by producing hypoglycemia, which is used to evaluate the pituitary growth hormone reserve. increases the intracellular shift of potassium and magnesium and decreases renal excretion of sodium. decreases the synthesis of high-density lipoprotein [HDL] cholesterol and increases the synthesis of very-low-density lipoprotein [VLDL] cholesterol in the liver. increases lipoprotein uptake and utilization in the lactating mammary gland. stimulates the activity of and tissue response to the sympathetic nervous system.

ADME

Pharmacokinetics & PD

Onset	Minutes–hours (formulation-dependent)
Duration	Hours–>40 h (basal analogues)
Route	INTRAVENOUS, SUBCUTANEOUS
Absorption	and Bioavailability Pharmacokinetic profiles in healthy volunteers and patients with diabetes (type 1 or type 2) demonstrated that absorption of insulin glulisine was faster than that of regular human insulin. In a study in patients with type 1 diabetes (n=20) after subcutaneous...
Metabolism	is the primary activity of insulins and insulin analogs, including insulin glulisine. Insulins lower blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis and enh...
Half-life	of 42 minutes compared to 86 minutes. Specific Populations Pediatric patients The pharmacokinetic and pharmacodynamic properties of APIDRA and regular human insulin were assessed in a study conducted in pediatric patients 7 to 11 years old (n=10) and 12 to 16 years old (n=10) wit...

Full PK/PD text

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Regulation of glucose metabolism is the primary activity of insulins and insulin analogs, including insulin glulisine. Insulins lower blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis and enhance protein synthesis. 12.2 Pharmacodynamics Studies in healthy volunteers and patients with diabetes demonstrated that APIDRA has a more rapid onset of action and a shorter duration of activity than regular human insulin when given subcutaneously. In a study in patients with type 1 diabetes (n=20), the glucose-lowering profiles of APIDRA and regular human insulin were assessed at various times in relation to a standard meal at a dose of 0.15 units/kg (see Figure 1 ). The maximum blood glucose excursion (ΔGLU max ; baseline subtracted glucose concentration) for APIDRA injected 2 minutes before a meal was 65 mg/dL compared to 64 mg/dL for regular human insulin injected 30 minutes before a meal (see Figure 1A ), and 84 mg/dL for regular human insulin injected 2 minutes before a meal (see Figure 1B ). The maximum blood glucose excursion for APIDRA injected 15 minutes after the start of a meal was 85 mg/dL compared to 84 mg/dL for regular human insulin injected 2 minutes before a meal (see Figure 1C ). Figure 1: Serial mean blood glucose collected up to 6 hours following a single dose of APIDRA and regular human insulin. APIDRA given 2 minutes (APIDRA - pre) before the start of a meal compared to regular human insulin given 30 minutes (Regular - 30 min) before start of the meal (see Figure 1A ) and compared to regular human insulin (Regular - pre) given 2 minutes before a meal (see Figure 1B ). APIDRA given 15 minutes (APIDRA - post) after start of a meal compared to regular human insulin (Regular - pre) given 2 minutes before a meal (see Figure 1C ). On the x-axis, zero (0) is the start of a 15-minute meal. In a randomized, open-label, two-way crossover study, 16 healthy male subjects received an intravenous infusion of APIDRA or regular human insulin with saline diluent at a rate of 0.8 milliunits/kg/min for two hours. Infusion of the same dose of APIDRA or regular human insulin produced equivalent glucose disposal at steady state. Figure 1A Figure 1B Figure 1C Figure 12.3 Pharmacokinetics Absorption and Bioavailability Pharmacokinetic profiles in healthy volunteers and patients with diabetes (type 1 or type 2) demonstrated that absorption of insulin glulisine was faster than that of regular human insulin. In a study in patients with type 1 diabetes (n=20) after subcutaneous administration of 0.15 units/kg, the median time to maximum concentration (T max ) was 60 minutes (range 40 to 120 minutes) and the peak concentration (C max ) was 83 microunits/mL (range 40 to 131 microunits/mL) for insulin glulisine compared to a median T max of 120 minutes (range 60 to 239 minutes) and a C max of 50 microunits/mL (range 35 to 71 microunits/mL) for regular human insulin (see Figure 2 ). Figure 2: Pharmacokinetic Profiles of Insulin Glulisine and Regular Human Insulin in Patients with Type 1 Diabetes after a Dose of 0.15 units/kg. Insulin glulisine and regular human insulin were administered subcutaneously at a dose of 0.2 units/kg in a euglycemic clamp study in patients with type 2 diabetes (n=24) and a body mass index (BMI) between 20 and 36 kg/m 2 . The median time to maximum concentration (T max ) was 100 minutes (range 40 to 120 minutes) and the median peak concentration (C max ) was 84 microunits/mL (range 53 to 165 microunits/mL) for insulin glulisine compared to a median T max of 240 minutes (range 80 to 360 minutes) and a median C max of 41 microunits/mL (range 33 to 61 microunits/mL) for regular human insulin (see Figure 3 ). Figure 3: Pharmacokinetic Profiles of Insulin Glulisine and Regular Human Insulin in Patients with Type 2 Diabetes after a Subcutaneous Dose of 0.2 units/kg. When APIDRA was injected subcutaneously into different areas of the body, the time-concentration profiles were similar. The absolute bioavailability of insulin glulisine after subcutaneous administration is approximately 70%, regardless of injection area (abdomen 73%, deltoid 71%, thigh 68%). In a clinical study in healthy volunteers (n=32) the total insulin glulisine bioavailability was similar after subcutaneous injection of insulin glulisine and NPH insulin (premixed in the syringe) and following separate simultaneous subcutaneous injections. There was 27% attenuation of the maximum concentration (C max ) of APIDRA after premixing; however, the time to maximum concentration (T max ) was not affected. Figure 2 Figure 3 Distribution and Elimination The distribution and elimination of insulin glulisine and regular human insulin after intravenous administration are similar with volumes of distribution of 13 and 21 L and half-lives of 13 and 17 minutes, respectively. After subcutaneous administration, insulin glulisine is eliminated more rapidly than regular human insulin with an apparent half-life of 42 minutes compared to 86 minutes. Specific Populations Pediatric patients The pharmacokinetic and pharmacodynamic properties of APIDRA and regular human insulin were assessed in a study conducted in pediatric patients 7 to 11 years old (n=10) and 12 to 16 years old (n=10) with type 1 diabetes. The relative differences in pharmacokinetics and pharmacodynamics between APIDRA and regular human insulin in these patients with type 1 diabetes were similar to those in healthy adult subjects and adults with type 1 diabetes. Race A study in 24 healthy Caucasians and Japanese subjects compared the pharmacokinetics and pharmacodynamics after subcutaneous injection of insulin glulisine, insulin lispro, and regular human insulin. With subcutaneous injection of insulin glulisine, Japanese subjects had a greater initial exposure (33%) for the ratio of AUC (0–1h) to AUC (0–clamp end) than Caucasians (21%) although the total exposures were similar. There were similar findings with insulin lispro and regular human insulin. Obesity Insulin glulisine and regular human insulin were administered subcutaneously at a dose of 0.3 units/kg in a euglycemic clamp study in obese, non-diabetic subjects (n=18) with a body mass index (BMI) between 30 and 40 kg/m 2 . The median time to maximum concentration (T max ) was 85 minutes (range 49 to 150 minutes) and the median peak concentration (C max ) was 192 microunits/mL (range 98 to 380 microunits/mL) for insulin glulisine compared to a median T max of 150 minutes (range 90 to 240 minutes) and a median C max of 86 microunits/mL (range 43 to 175 microunits/mL) for regular human insulin. The more rapid onset of action and shorter duration of activity of APIDRA and insulin lispro compared to regular human insulin were maintained in an obese non-diabetic population (n=18) (see Figure 4 ). Figure 4: Glucose Infusion Rates (GIR) in a Euglycemic Clamp Study after Subcutaneous Injection of 0.3 units/kg of APIDRA, Insulin Lispro or Regular Human Insulin in an Obese Population. Figure 4 Renal impairment Studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. In a study performed in 24 non-diabetic subjects with normal renal function (Cl Cr >80 mL/min), moderate renal impairment (30–50 mL/min), and severe renal impairment (<30 mL/min), the subjects with moderate and severe renal impairment had increased exposure to insulin glulisine by 29% to 40% and reduced clearance of insulin glulisine by 20% to 25% compared to subjects with normal renal function [see Use in Specific Populations (8.6) ] . Hepatic impairment The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of APIDRA has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure [see Use in Specific Populations (8.7) ] . Gender The effect of gender on the pharmacokinetics and pharmacodynamics of APIDRA has not been studied. Smoking The effect of smoking on the pharmacokinetics and pharmacodynamics of APIDRA has not been studied.

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Special populations

Pregnancy & lactation

Pregnancy

8.1 Pregnancy Risk Summary Available pharmacovigilance data have not established an association with insulin glulisine use during pregnancy and major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations ) . Animal reproduction studies have been conducted 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/day (2 times the average human dose, based on body surface area comparison) and to rabbits during organogenesis at subcutaneous doses up to 1.5 units/kg/day (0.5 times the average human dose, based on body surface area comparison). The effects did not differ from those observed with subcutaneous regular human insulin (see Data ) . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a peri-conceptional HbA1c >7 and has been reported to be as high as 20% to 25% in women with a peri-conceptional HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. Clinical Considerations Disease-associated maternal and/or embryo-fetal risk Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia-related morbidity. Data Animal data Insulin glulisine was given to pregnant female rabbits during gestation at doses up to 1.5 units/kg/day, resulting in an exposure 0.5 times the average human dose, based on body surface area. Adverse effects on embryo-fetal development, including postimplantation loss and skeletal defects, were observed at dose levels that caused maternal hypoglycemia and mortality. Insulin glulisine given to pregnant female rats during gestation at doses up to 10 units/kg/day, resulting in an exposure 2 times the average human dose based on body surface area, resulted in maternal toxicity indicative of hypoglycemia but did not adversely affect embryo-fetal development. Postnatal development was not adversely affected following administration of insulin glulisine to pregnant female rats during gestation and throughout lactation at doses up to 8 units/kg/day. The effects of insulin glulisine did not differ from those observed with regular human insulin used as a comparator in the same studies and administered at the same doses.

Lactation

8.1 Pregnancy Risk Summary Available pharmacovigilance data have not established an association with insulin glulisine use during pregnancy and major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations ) . Animal reproduction studies have been conducted 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/day (2 times the average human dose, based on body surface area comparison) and to rabbits during organogenesis at subcutaneous doses up to 1.5 units/kg/day (0.5 times the average human dose, based on body surface area comparison). The effects did not differ from those observed with subcutaneous regular human insulin (see Data ) . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a peri-conceptional HbA1c >7 and has been reported to be as high as 20% to 25% in women with a peri-conceptional HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. Clinical Considerations Disease-associated maternal and/or embryo-fetal risk Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia-related morbidity. Data Animal data Insulin glulisine was given to pregnant female rabbits during gestation at doses up to 1.5 units/kg/day, resulting in an exposure 0.5 times the average human dose, based on body surface area. Adverse effects on embryo-fetal development, including postimplantation loss and skeletal defects, were observed at dose levels that caused maternal hypoglycemia and mortality. Insulin glulisine given to pregnant female rats during gestation at doses up to 10 units/kg/day, resulting in an exposure 2 times the average human dose based on body surface area, resulted in maternal toxicity indicative of hypoglycemia but did not adversely affect embryo-fetal development. Postnatal development was not adversely affected following administration of insulin glulisine to pregnant female rats during gestation and throughout lactation at doses up to 8 units/kg/day. The effects of insulin glulisine did not differ from those observed with regular human insulin used as a comparator in the same studies and administered at the same doses. 8.2 Lactation Risk Summary Available data from published literature suggest that human insulin products, including APIDRA, are transferred into human milk. There are no adverse reactions reported in the breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including APIDRA, on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for APIDRA and any potential adverse effects on the breastfed infant from APIDRA or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of APIDRA to improve glycemic control have been established in pediatric patients. Use of APIDRA for this indication is supported by evidence from an active-controlled non-inferiority study in pediatric patients 4 years of age and older with type 1 diabetes mellitus treated with APIDRA (n=271) and from studies in adults with diabetes mellitus [see Clinical Pharmacology (12.3) , and Clinical Studies (14) ] . In the clinical trials, pediatric patients with type 1 diabetes mellitus had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to adults with type 1 diabetes mellitus [see Adverse Reactions (6.1) ] . 8.5 Geriatric Use In clinical trials, APIDRA was administered to 147 patients ≥65 years of age and 27 patients ≥75 years of age. The majority of this small subset of geriatric 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. In geriatric patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to reduce the risk of hypoglycemia [see Warnings and Precautions (5.3) ] . 8.6 Renal Impairment Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent APIDRA dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ] . 8.7 Hepatic Impairment Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent APIDRA dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ] .

Trust

Sources & disclaimer

Source: Local active-ingredient clinical extract; FDA drug label via OpenFDA/DailyMed; Professional class pharmacology (Insulin (antidiabetic hormone))

Open source link

Clinical review date not recorded.

Decision support only — not a substitute for clinical judgment, product SmPC, or Kenya STG/EML.