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Insulin lispro - humalog® 

Onset:  15 – 30 min Peak: 0.5 – 2.5 hrs Duration: 2-4 hours  (max: ≤5 hrs) Solution:  Clear
Comments: Must be taken just before or immediately after eating.  Chemically, insulin lispro Lys(B28), Pro(B29) is created when the amino acids at positions 28 and 29 on the insulin Beta-chain are reversed. Insulin lispro (Humalog) and insulin aspart (Novolog), when administered intravenously, show pharmacodynamic parameters similar to regular insulin.  A dose of lispro insulin peaks in one half the time and double the concentration of a comparable subcutaneous injection of human regular insulin.    Lispro insulin should be injected immediately prior to eating (or less than 15 minutes before the meal). Injecting lispro 30-60 minutes before the meal can result in hypoglycemia.
Mixing
NPH:  If Humalog is mixed with NPH human insulin, Humalog should be drawn into the syringe first. The injection should be made immediately after mixing.   
  
Regular: Compatible – but NO support clinically for such a mixture.  Draw up Humalog first before drawing up Regular Insulin.

If Humalog is mixed with a longer-acting insulin, such as Humulin N or Humulin U, Humalog should be drawn into the syringe first to prevent clouding of the Humalog by the longer-acting insulin. Injection should be made immediately after mixing. Mixtures should not be administered intravenously. Mixing Humalog with Humulin N or U does not decrease the absorption rate or the total bioavailability of Humalog.   Mixing Lispro: Lispro insulin may be mixed with NPH, Lente or Ultralente. Any mixture should be given 15 minutes before the meal and immediately after mixing. 

INDICATIONS AND USAGE
Humalog is an insulin analog that is indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia. Humalog has a more rapid onset and a shorter duration of action than Regular human insulin. Therefore, in patients with type 1 diabetes, Humalog should be used in regimens that include a longer–acting insulin. However, in patients with type 2 diabetes, Humalog may be used without a longer–acting insulin when used in combination therapy with sulfonylurea agents.

Humalog may be used in an external insulin pump, but should not be diluted or mixed with any other insulin when used in the pump.

CLINICAL PHARMACOLOGY
Antidiabetic Activity
The primary activity of insulin, including Humalog, is the regulation of glucose metabolism. In addition, all insulins have several anabolic and anti–catabolic actions on many tissues in the body. In muscle and other tissues (except the brain), insulin causes rapid transport of glucose and amino acids intracellularly, promotes anabolism, and inhibits protein catabolism. In the liver, insulin promotes the uptake and storage of glucose in the form of glycogen, inhibits gluconeogenesis, and promotes the conversion of excess glucose into fat.

Humalog has been shown to be equipotent to human insulin on a molar basis. One unit of Humalog has the same glucose–lowering effect as one unit of Regular human insulin, but its effect is more rapid and of shorter duration. The glucose–lowering activity of Humalog and Regular human insulin is comparable when administered to nondiabetic subjects by the intravenous route.


Pharmacokinetics —————————————————————
Absorption and Bioavailability
Humalog is as bioavailable as Regular human insulin, with absolute bioavailability ranging between 55% to 77% with doses between 0.1 to 0.2 U/kg, inclusive. Studies in nondiabetic subjects and patients with type 1 (insulin–dependent) diabetes demonstrated that Humalog is absorbed faster than Regular human insulin (U–100) (see Figure 1). In nondiabetic subjects given subcutaneous doses of Humalog ranging from 0.1 to 0.4 U/kg, peak serum concentrations were observed 30 to 90 minutes after dosing. When nondiabetic subjects received equivalent doses of Regular human insulin, peak insulin concentrations occurred between 50 to 120 minutes after dosing. Similar results were seen in patients with type 1 diabetes. The pharmacokinetic profiles of Humalog and Regular human insulin are comparable to one another when administered to nondiabetic subjects by the intravenous route. Humalog was absorbed at a consistently faster rate than Regular human insulin in healthy male volunteers given 0.2 U/kg Regular human insulin or Humalog at abdominal, deltoid, or femoral subcutaneous sites, the three sites often used by patients with diabetes. After abdominal administration of Humalog, serum drug levels are higher and the duration of action is slightly shorter than after deltoid or thigh administration (see DOSAGE AND ADMINISTRATION). Humalog has less intra– and inter–patient variability compared with Regular human insulin.

Distribution
The volume of distribution following injection of Humalog is identical to that of Regular human insulin, with a range of 0.26 to 0.36 L/kg.

Metabolism
Human metabolism studies have not been conducted. However, animal studies indicate that the metabolism of Humalog is identical to that of Regular human insulin.

Elimination
When Humalog is given subcutaneously, its t1/2 is shorter than that of Regular human insulin (1 versus 1.5 hours, respectively). When given intravenously, Humalog and Regular human insulin show identical dose–dependent elimination, with a t1/2 of 26 and 52 minutes at 0.1 U/kg and 0.2 U/kg, respectively.

Pharmacodynamics
Studies in nondiabetic subjects and patients with diabetes demonstrated that Humalog has a more rapid onset of glucose–lowering activity, an earlier peak for glucose–lowering, and a shorter duration of glucose–lowering activity than Regular human insulin. The earlier onset of activity of Humalog is directly related to its more rapid rate of absorption. The time course of action of insulin and insulin analogs, such as Humalog, may vary considerably in different individuals or within the same individual.  The rate of insulin absorption and consequently the onset of activity is known to be affected by the site of injection, exercise, and other variables


Special Populations————————-
Age and Gender
Information on the effect of age and gender on the pharmacokinetics of Humalog is unavailable. However, in large clinical trials, sub-group analysis based on age and gender did not indicate any difference in postprandial glucose parameters between Humalog and Regular human insulin.

Smoking
The effect of smoking on the pharmacokinetics and pharmacodynamics of Humalog has not been studied.

Pregnancy
The effect of pregnancy on the pharmacokinetics and pharmacodynamics of Humalog has not been studied.

Obesity
The effect of obesity and/or subcutaneous fat thickness on the pharmacokinetics and pharmacodynamics of Humalog has not been studied. In large clinical trials, which included patients with Body Mass Index up to and including 35 kg/m2, no consistent differences were observed between Humalog and Humulin® R with respect to postprandial glucose parameters.

Renal Impairment
Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. In a study of 25 patients with type 2 diabetes and a wide range of renal function, the pharmacokinetic differences between Humalog and Regular human insulin were generally maintained. However, the sensitivity of the patients to insulin did change, with an increased response to insulin as the renal function declined. Careful glucose monitoring and dose reductions of insulin, including Humalog, may be necessary in patients with renal dysfunction.

Hepatic Impairment
Some studies with human insulin have shown increased circulating levels of insulin in patients with hepatic failure. In a study of 22 patients with type 2 diabetes, impaired hepatic function did not affect the subcutaneous absorption or general disposition of Humalog when compared with patients with no history of hepatic dysfunction. In that study, Humalog maintained its more rapid absorption and elimination when compared with Regular human insulin. Careful glucose monitoring and dose adjustments of insulin, including Humalog, may be necessary in patients with hepatic dysfunction.

CONTRAINDICATIONS
Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to Humalog or any of its excipients.

WARNINGS
This human insulin analog differs from Regular human insulin by its rapid onset of action as well as a shorter duration of activity. When used as a meal-time insulin, the dose of Humalog should be given within 15 minutes before or immediately after the meal. Because of the short duration of action of Humalog, patients with type 1 diabetes also require a longer–acting insulin to maintain glucose control (except when using an external insulin pump). Glucose monitoring is recommended for all patients with diabetes and is particularly important for patients using an external insulin pump.

Hypoglycemia is the most common adverse effect associated with insulins, including Humalog. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose monitoring is recommended for all patients with diabetes.

Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type (e.g., Regular, NPH, analog), species, or method of manufacture may result in the need for a change in dosage.

External Insulin Pumps: When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin. Patients should carefully read and follow the external insulin pump manufacturer’s instructions and the Patient Information leaflet before using Humalog.

Physicians should carefully evaluate information on external insulin pump use in this Humalog physician package insert and in the external insulin pump manufacturer’s instructions. If unexplained hyperglycemia or ketosis occurs during external insulin pump use, prompt identification and correction of the cause is necessary. The patient may require interim therapy with subcutaneous insulin injection


PRECAUTIONS
General
Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated with the use of all insulins. Because of differences in the action of Humalog and other insulins, care should be taken in patients in whom such potential side effects might be clinically relevant (e.g., patients who are fasting, have autonomic neuropathy, or are using potassium–lowering drugs or patients taking drugs sensitive to serum potassium level). Lipodystrophy and hypersensitivity are among other potential clinical adverse effects associated with the use of all insulins.

As with all insulin preparations, the time course of Humalog action may vary in different individuals or at different times in the same individual and is dependent on site of injection, blood supply, temperature, and physical activity.

Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan. Insulin requirements may be altered during illness, emotional disturbances, or other stress.

Hypoglycemia — As with all insulin preparations, hypoglycemic reactions may be associated with the administration of Humalog. Rapid changes in serum glucose concentrations may induce symptoms of 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 long duration of diabetes, diabetic nerve disease, use of medications such as beta–blockers, or intensified diabetes control.

Renal Impairment — The requirements for insulin may be reduced in patients with renal impairment.

Hepatic Impairment — Although impaired hepatic function does not affect the absorption or disposition of Humalog, careful glucose monitoring and dose adjustments of insulin, including Humalog, may be necessary.

Allergy — Local Allergy — As with any insulin therapy, patients may experience redness, swelling, or itching at the site of injection. These minor reactions usually resolve in a few days to a few weeks. In some instances, these reactions may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique.

Systemic Allergy — Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic reaction, may be life threatening. In controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving Humulin R (N=2969) and 30 patients receiving Humalog (N=2944) (p=0.053). Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient.

Antibody Production — In large clinical trials, antibodies that cross–react with human insulin and insulin lispro were observed in both Humulin R– and Humalog–treatment groups. As expected, the largest increase in the antibody levels during the 12–month clinical trials was observed with patients new to insulin therapy.

Usage in External Insulin Pumps — The infusion set (reservoir syringe, tubing, and catheter), Disetronic® D–TRON®2,3 or D–TRON®2,3plus cartridge adapter, and Humalog in the external insulin pump reservoir should be replaced and a new infusion site selected every 48 hours or less. Humalog in the external insulin pump should not be exposed to temperatures above 37°C (98.6°F).

In the D–TRON®2,3 or D–TRON®2,3plus pump, Humalog 3 mL cartridges may be used for up to 7 days. However, as with other external insulin pumps, the infusion set should be replaced and a new infusion site should be selected every 48 hours or less.

When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin


DOSAGE AND ADMINISTRATION
Humalog is intended for subcutaneous administration, including use in select external insulin pumps (see DOSAGE AND ADMINISTRATION, External Insulin Pumps). Dosage regimens of Humalog will vary among patients and should be determined by the healthcare provider familiar with the patient’s metabolic needs, eating habits, and other lifestyle variables. Pharmacokinetic and pharmacodynamic studies showed Humalog to be equipotent to Regular human insulin (i.e., one unit of Humalog has the same glucose–lowering effect as one unit of Regular human insulin), but with more rapid activity. The quicker glucose–lowering effect of Humalog is related to the more rapid absorption rate from subcutaneous tissue. An adjustment of dose or schedule of basal insulin may be needed when a patient changes from other insulins to Humalog, particularly to prevent pre–meal hyperglycemia.

When used as a meal–time insulin, Humalog should be given within 15 minutes before or immediately after a meal. Regular human insulin is best given 30 to 60 minutes before a meal. To achieve optimal glucose control, the amount of longer–acting insulin being given may need to be adjusted when using Humalog.

The rate of insulin absorption and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables. Humalog was absorbed at a consistently faster rate than Regular human insulin in healthy male volunteers given 0.2 U/kg Regular human insulin or Humalog at abdominal, deltoid, or femoral sites, the three sites often used by patients with diabetes. When not mixed in the same syringe with other insulins, Humalog maintains its rapid onset of action and has less variability in its onset of action among injection sites compared with Regular human insulin (see PRECAUTIONS). After abdominal administration, Humalog concentrations are higher than those following deltoid or thigh injections. Also, the duration of action of Humalog is slightly shorter following abdominal injection, compared with deltoid and femoral injections. As with all insulin preparations, the time course of action of Humalog may vary considerably in different individuals or within the same individual. Patients must be educated to use proper injection techniques.

Humalog in a vial may be diluted with STERILE DILUENT for Humalog®, Humulin® N, Humulin® R, Humulin® 70/30, and Humulin® R U-500 to a concentration of 1:10 (equivalent to U–10) or 1:2 (equivalent to U–50). Diluted Humalog may remain in patient use for 28 days when stored at 5°C (41°F) and for 14 days when stored at 30°C (86°F). Do not dilute Humalog contained in a cartridge or Humalog used in an external insulin pump.

Parenteral drug products should be inspected visually before use whenever the solution and the container permit. If the solution is cloudy, contains particulate matter, is thickened, or is discolored, the contents must not be injected. Humalog should not be used after its expiration date.

The cartridge containing Humalog is not designed to allow any other insulin to be mixed in the cartridge or for the cartridge to be refilled with insulin.

External Insulin Pumps — Humalog was tested in MiniMed®1 Models 506, 507, and 508 insulin pumps using MiniMed®1 Polyfin®1 infusion sets. Humalog was also tested in the Disetronic®2 H–TRONplus® V100 insulin pump (with plastic 3.15 mL insulin reservoir) and the Disetronic D–TRON®2,3 and D–TRON®2,3plus pumps (with Humalog 3 mL cartridges) using Disetronic Rapid®2 infusion sets.

Humalog should not be diluted or mixed with any other insulin when used in an external insulin pump.


Storage — Unopened Humalog should be stored in a refrigerator [2° to 8°C (36° to 46°F)], but not in the freezer. Do not use Humalog if it has been frozen. Unrefrigerated [below 30°C (86°F)] vials, cartridges, Pens, and Humalog KwikPen must be used within 28 days or be discarded, even if they still contain Humalog. Protect from direct heat and light. See table below:

 

Not In-Use (Unopened) Room Temperature [Below 30°C (86°F)]

Not In-Use (Unopened) Refrigerated

In-Use (Opened) Room Temperature, [Below 30°C (86°F)]

 10 mL Vial and 3 mL Vial

28 days

Until expiration date

28 days, refrigerated/room temperature.

 3 mL Cartridge

28 days

Until expiration date

28 days, Do not refrigerate.

 3 mL Pen and Humalog KwikPen (prefilled)

28 days

Until expiration date

28 days, Do not refrigerate.

Use in an External Insulin Pump — A Humalog 3 mL cartridge used in the D–TRON®2,3 or D–TRON®2,3plus should be discarded after 7 days, even if it still contains Humalog. Infusion sets, D–TRON®2,3 and D–TRON®2,3plus cartridge adapters, and Humalog in the external insulin pump reservoir should be discarded every 48 hours or less.

Insulin glulisine- apidra® 

Onset:  12 – 30 min Peak: 1.6 – 2.8  hrs Duration: 3-4 hours Solution:  Clear
Comments: Insulin glulisine should be administered within 15 minutes before or within 20 minutes after starting a meal.   APIDRA® (insulin glulisine [rDNA origin] injection) is a rapid-acting human insulin analog used to lower blood glucose. Insulin glulisine is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12). Insulin glulisine 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.  APIDRA® (insulin glulisine) 30-60 minutes before the meal can result in hypoglycemia.
Mixing
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.

INDICATIONS AND USAGE
APIDRA is a rapid acting human insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus.

DOSAGE AND ADMINISTRATION
The dosage of APIDRA must be individualized:

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.
Continuous Subcutaneous Infusion Pump APIDRA must not be mixed or diluted when used in an external insulin infusion pump.
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.

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.

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

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 pumps1 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.

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

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.

DOSAGE FORMS AND STRENGTHS
APIDRA 100 units/mL (U-100) is available as:

  • 10 mL vials
  • 3 mL cartridge system for use in OptiClik ® (Insulin Delivery Device)
  • 3 mL SoloStar® prefilled pen

CONTRAINDICATIONS

  • Do not use during episodes of hypoglycemia
  • Do not use in patients with hypersensitivity to APIDRA or any of its excipients

WARNINGS AND PRECAUTIONS

  • Dose adjustment and monitoring: Closely monitor blood glucose in all patients treated with insulin. Change insulin regimens cautiously and only under medical supervision.
  • Hypoglycemia: Most common adverse reaction of insulin therapy and may be life-threatening
  • Allergic reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with any insulin, including APIDRA
  • Hypokalemia: All insulins, including APIDRA can cause hypokalemia, which if untreated, may result in respiratory paralysis, ventricular arrhythmia, and death
  • Renal or hepatic impairment: Like all insulins, may require a reduction in the APIDRA dose
  • 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
  • Pump use: Change the APIDRA in the pump reservoir every 48 hours
  • Intravenous use: Frequently monitor for hypoglycemia and hypokalemia.

ADVERSE REACTIONS
Adverse reactions commonly associated with APIDRA include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, and rash.

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

DRUG INTERACTIONS

  • Certain drugs affect glucose metabolism and may necessitate insulin dose adjustment
  • The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine).

USE IN SPECIFIC POPULATIONS
APIDRA has not been studied in children under 4 years of age

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.

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.

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. 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.

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.


CLINICAL PHARMACOLOGY

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.

The glucose lowering activities of APIDRA and of regular human insulin are equipotent when administered by the intravenous route. After subcutaneous administration, the effect of APIDRA is more rapid in onset and of shorter duration compared to regular human insulin.

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.

The maximum blood glucose excursion (deltaGLUmax; 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, and 84 mg/dL for regular human insulin injected 2 minutes before a meal. 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.

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

Unopened Vial/Cartridge System/SoloStar
Unopened APIDRA vials, cartridge systems 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/cartridge systems/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) Cartridge System:
The opened (in-use) cartridge system inserted in OptiClik® should NOT be refrigerated but should be kept below 77°F (25°C) away from direct heat and light. The opened (in-use) cartridge system must be discarded after 28 days. Do not store OptiClik®, with or without cartridge system, in a refrigerator at any time.

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 should 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.

Preparation and handling
After dilution for intravenous use, the solution should be inspected visually for particulate matter and discoloration prior to administration. Do not use the solution if it has become cloudy or contains particles; use only if it is clear and colorless. APIDRA is not compatible with Dextrose solution and Ringers solution and, therefore, cannot be used with these solution fluids. The use of APIDRA with other solutions has not been studied and is, therefore, not recommended.

Cartridge system: If OptiClik® (the Insulin Delivery Device for APIDRA) malfunctions, APIDRA may be drawn from the cartridge system into a U-100 syringe and injected.

 afrezza ® (insulin human) inhalation powder 

Drug UPDATES:  AFREZZA ® (insulin human) Inhalation Powder
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2014

Mechanism of Action: Insulin lowers blood glucose levels by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in adipocytes, inhibits proteolysis, and enhances protein synthesis.

INDICATIONS AND USAGE:
AFREZZA® is a rapid acting inhaled insulin indicated to improve glycemic control in adult patients with diabetes mellitus.

Important limitations of use:
In patients with type 1 diabetes, must use with a long-acting insulin.
Not recommended for the treatment of diabetic ketoacidosis.
Not recommended in patients who smoke.

HOW SUPPLIED:
AFREZZA is available as single-use cartridges of:
4 units
8 units
12 units

Reference(s)

National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
Provides access to the latest drug monographs submitted to the Food and Drug Administration (FDA). Please review the latest applicable package insert for additional information and possible updates.  A local search option of this data can be found here.

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