Vademecum

INSULINA

Description: Insulin is a pancreatic hormone. It is secreted by the pancreatic beta-cells of the islets of Langerhans and is essential for the metabolism of glucose and for the homeostasis of blood glucose. Direct evidence of a pancreatic contribution to blood glucose regulation was first discovered in 1889. Some time later, an extract from the pancreatic beta-cells of the islets of Langerhans revealed effectiveness in lowering elevated blood glucose concentrations. This active extract (insulin) was administered to a young diabetic patient in 1922, and daily injections of the hormonal replacement therapy were found to reverse the otherwise fatal metabolic disorder. FDA approval of insulin products began in 1939. The precise amino acid sequence of insulin was established in 1960, leading to complete synthesis of the hormone by 1963. The first biosynthetic human insulin was given FDA approval in 1982. Bovine, porcine, and recombinant human insulin preparations are currently available for use in diabetic patients worldwide; however, bovine-tissue derived insulin is no longer on the US market as of 1999, due to FDA concerns over the transmission of bovine spongiform encephalopathy (i.e., "mad-cow disease"). While regular (short-acting) and NPH (intermediate-acting) human insulin are the most commonly used insulin preparations, several new developments in insulin analog formulation will offer further treatment options. Insulin lispro (Humalogï¿½), a rapid-onset regular insulin analog, was FDA-approved in June 1996. Velosulinï¿½ BR, a buffered regular insulin, was approved in July 1999. Humalogï¿½Mixï¿½, a combination of insulin lispro protamine in combination with insulin lispro, was approved in early 2000. Insulin glargine (i.e., Lantusï¿½, Aventis Pharma), the first long-acting, once daily human insulin analog, was approved by the FDA in April 2000. Insulin aspart (NovoLogï¿½), another rapid-onset regular insulin analog similar to insulin lispro, was approved by the FDA in June 2000. Several new injectable insulin formulations continue to be investigated, with FDA approvals expected after the year 2000. Both Eli Lilly and NovoNordisk are in early clinical development of insulin fatty acid acylated analogs that bind to serum albumin resulting in a flatter time-action profile than NPH insulin (i.e., WW99-S32, Lilly and NN304, Novo Nordisk). Alternative routes for administering insulin are also being evaluated. A dry powder orally inhaled dosage form completed phase IIb investigation as of June 1998 in patients with both Type I and Type II diabetes mellitus. Using a device similar to an asthma inhaler, the powder is administered in a fixed dosage prior to meals; some patients in studies to date supplemented inhalations of insulin with a long-acting insulin injection (e.g., Ultralente) administered at bedtime. Studies to date reveal that inhaled insulin performs as well as injectable regular insulin. Pfizer Inc. is developing this inhaled insulin in collaboration with Inhaled Therapeutics Systems, Inc. and Aventis. As of mid-2000, phase III trials of orally inhaled insulin were in progress. The FDA is also considering an IND for a sublingual/buccal insulin dosage form called Oralinï¿½; this product is currently in phase III trials in Canada. Mechanism of Action: Endogenous insulin stimulates carbohydrate metabolism in cardiac, skeletal, and adipose tissue by facilitating the uptake of glucose by these cells. Other tissues, such as nerve, intestinal, liver, and kidney tubules, do not require insulin for glucose transport, but liver cells do need insulin to convert glucose to glycogen (for storage). Insulin also enhances lipogenesis, increases protein synthesis, and inhibits lipolysis and free fatty acid release from adipose tissues. Commercially available insulin is prepared using recombinant DNA technology (E. coli bacteria) or enzymatic modification of beef or pork insulin to create a product identical in structure and function to endogenous human insulin. Biosynthetic insulin is used as replacement therapy in patients with diabetes mellitus (Type I, or IDDM; and Type II, or NIDDM) to temporarily restore their ability to use fats, carbohydrates, and proteins, and to convert glycogen to fat. Insulin administration also enables these patients to replete their liver glycogen stores. Pharmacokinetics: Regular insulin is currently administered via the intravenous or subcutaneous routes. Investigational routes for regular insulin include oral inhalation dosage forms and sublingual or buccal administration. All other formulations of insulin are administered via the subcutaneous route only. Insulin distributes widely throughout the body. A small portion is inactivated by peripheral tissues, but the majority is metabolized by the liver and kidneys. Insulin is filtered and reabsorbed by the kidneys; the plasma half-life of human insulin is approximately 9 minutes. A variety of insulin preparations are available; all have different times to onset of activity and durations of action. The profiles of insulin are prolonged by adding zinc ions (e.g., Lente insulin), by combination with protamine (e.g., Human insulin lispro protamine, NPH insulin), or by the production of an insulin analog that either shortens the duration of action of the insulin moeity (i.e., insulin lispro, insulin aspart) or prolongs it (e.g., insulin glargine). The following discusses the pharmacokinetic differences (onset, peak, duration) of each insulin type: Rapid-Acting Insulins: ï¿½Regular insulin: The onset of action begins approximately 30 minutes after SC administration and the duration lasts roughly 8ï¿½12 hours. Regular insulin is best given 30ï¿½60 minutes before a meal. Maximal effects are seen in 1ï¿½3 hours; the plasma half-life following SC administration is roughly 1.5 hours. After IV administration, the onset of regular insulin is within 15 minutes and the duration is decreased to 30ï¿½60 minutes. Maximal effects occur within 15ï¿½30 minutes after IV injection. The plasma half-life following IV administration is roughly 9 minutes. Regular insulin can be used for administration via external SC insulin infusion pumps. ï¿½Buffered regular insulin: The pharmacokinetics of this insulin are identical to those of regular insulin administered by the SC route. This insulin is for SC use only, and should not be mixed with other insulins due to the phosphate buffer. The buffering allows better compatability (i.e., less aggregation in catheters) with some external infusion technologies when administered via external SC insulin infusion pumps. ï¿½Insulin aspart: A chemical modification of regular human insulin where the amino acid proline at position B28 is replaced by aspartic acid produces this rapid-acting insulin analog. Pharmacodynamically, when compared to regular insulin, insulin aspart has a more rapid onset of glucose-lowering activity (roughly 15 minutes) and an earlier peak glucose lowering effect after SC administration. It is similar in onset to insulin lispro. Insulin aspart reaches mean peak plasma levels faster (40ï¿½50 minutes) than regular insulin (60ï¿½120 minutes) when given SC. Intermittent SC injections of insulin aspart should be given within 5ï¿½10 minutes prior to a meal because of the fast onset compared to regular insulin. Compared to regular insulin, insulin aspart exhibits a shorter duration of action, roughly 3ï¿½5 hours. This insulins is not recommended for IV administration. ï¿½Insulin lispro: A chemical modification of regular human insulin where the position of 2 amino acids are reversed produces this rapid-acting insulin analog. Pharmacodynamically, when compared to regular insulin, insulin lispro has a more rapid onset of glucose-lowering activity (15ï¿½30 minutes) and an earlier peak glucose lowering effect after SC administration. It is similar in onset to insulin aspart. Insulin lispro reaches mean peak plasma concentrations faster (30ï¿½90 minutes) than regular insulin (60ï¿½120 minutes) when given SC. Intermittent SC injections of insulin lispro should be given within 15 minutes prior to a meal because of the fast onset compared to regular insulin. After abdominal administration, insulin lispro concentrations are higher than those following deltoid or thigh injections. Also, the duration of action of insulin lispro is slightly shorter following abdominal injection, compared with deltoid and femoral injections. Insulin lispro also has a shorter duration of action than regular insulin, roughly 3ï¿½5 hours. This insulin is not recommended for IV administration; however, insulin lispro exhibits similar pharmacokinetics to IV regular insulin when administered by the IV route; there is no advantage over regular insulin. Insulin lispro is a buffered insulin and is commonly used for insulin therapy in patients who wear external SC insulin infusion pumps. ï¿½Semilente insulin (prompt insulin zinc suspension): This is a rapid-acting insulin with an onset of action between 1 and 1.5 hours following SC administration, with peak effects occurring anywhere from 5ï¿½10 hours. The duration of semilente insulin ranges from 10ï¿½16 hours. Semilente insulin is not commonly used. This agent also can be administered alone when rapid action is desired, except in the case of diabetic coma or emergency situations, for which regular insulin is the drug of choice. Semilente insulin is administered SC and should not be administered by the IV route. Intermediate-Acting Insulins: ï¿½Human insulin lispro protamine (NPL insulin): Protamine is added to the insulin lispro analog to extend the onset and duration of action compared to regular human insulin lispro. The onset and duration of insulin lispro protamine alone is comparable to that of NPH insulin alone. Human insulin lispro protamine activity peaks at a mean of 5.8 hours (range 1.3ï¿½8.3 hours) after administration, and roughly 22% of the total activity occurs in the first 4 hours (range 6.3ï¿½40%). This agent should not be used for diabetic coma or in emergency situations. Human insulin lispro protamine is administered via the SC route by intermittent injections only, and is found in combination products with human insulin lispro. Combination with insulin lispro shortens the onset of action to that of insulin lispro, necessitating dosing within 15 minutes of a meal, and shortens the time to peak activity to a mean 2.3ï¿½2.5 hours (range 0.8ï¿½6.5 hours). ï¿½NPH insulin (isophane insulin suspension): NPH activity peaks at a mean of 5.5 hours (range 4ï¿½14 hours) after administration, and roughly 14% of the total activity occurs in the first 4 hours (range 3.0ï¿½48%). The duration of activity ranges from 10ï¿½24 hours or longer. This agent should not be used for diabetic coma or in emergency situations. NPH insulin is administered via the SC route by intermittent injections only. NPH is found in combination products with regular insulin. Combination with regular insulin shortens the time to peak activity to a mean 3.3ï¿½4.4 hours (range 1.5ï¿½16 hours). ï¿½Lente insulin (insulin zinc suspension): Lente insulin has an onset of action of 2ï¿½4 hours, and a duration of effect of roughly 12ï¿½24 hours following SC administration. The peak activity of lente insulin occurs 7ï¿½15 hours following administration. The lente insulin solution contains zinc, and must not be diluted or mixed with any other insulin or solution, as this would change the onset of action of the insulin. This agent should not be used in the case of diabetic coma or emergency situations. Lente insulin is administered is administered via intermittent SC injections only. Long-Acting Insulins: ï¿½Insulin glargine: A chemical modification of regular human insulin where the amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the C-terminus of the B-chain produces this long-acting insulin analog. The insulin glargine solution contains zinc, and must not be diluted or mixed with any other insulin or solution, as this would change the onset of action of the insulin. After injection into the subcutaneous tissue, the acidic solution is neutralized, leading to the formation of microprecipitates from which small amounts of insulin glargine are slowly released. Pharmacodynamically, when compared to NPH human insulin, insulin glargine exhibits a slower onset of glucose-lowering activity (roughly 5 hours) which does not peak; the constant effects of insulin glargine up to a median-24 hour period allow for once-daily dosing and to provide a patient's basal insulin. Insulin glargine should not be used in the case of diabetic coma or emergency situations. Insulin glargine is administered via intermittent SC injections only. ï¿½Ultralente insulin (extended insulin zinc suspension): is a long-acting insulin used in the management of diabetes mellitus. The drug's onset of action usually occurs within 4 hours, with peak activity occurring 10ï¿½30 hours after SC administration. The duration of effect typically ranges from 18ï¿½28 hours. The ultralente insulin solution contains zinc, and must not be diluted or mixed with any other insulin or solution, as this would change the onset of action of the insulin. Ultralente insulin should not be used in the case of diabetic coma or emergency situations. Ultralente insulin is administered via intermittent SC injections only. ï¿½PZI (protamine zinc insulin suspension): PZI is a long-acting insulin rarely used in the management of diabetes mellitus. The onset of action of this agent is approximately 4ï¿½8 hours, and the duration of action of roughly 36 hours. The peak effects occur 14ï¿½24 hours following SC administration. The PZI insulin solution contains zinc, and must not be diluted or mixed with any other insulin or solution, as this would change the onset of action of the insulin. PZI should not be used to treat diabetic coma or in emergency situations. PZI is administered via intermittent SC injections only.

Indications...Dosage For the treatment of diabetes mellitus type I or for the treatment of diabetes mellitus type II inadequately managed by diet and oral hypoglycemics: ï¿½general information on the daily insulin requirements, regardless of insulin type administered: Subcutaneous dosage: Adults and children: Insulin dosage requirements are highly variable and can range from 0.1ï¿½2.5 units/kg/day. Most patients generally require between 0.5ï¿½1.2 units/kg/day. Initial therapy can be less aggressive in Type II diabetics than for Type I diabetes. For Type I DM, the average initial dose is 0.5ï¿½0.6 units/kg/day. The average initial dose for Type II DM is 0.2ï¿½0.6 units/kg/day. Many with Type II DM can be initially controlled on less than 20 units/day. Dosage frequency depends on the type of insulin used and if infusion devices [e.g., subcutaneous insulin pumps] are used for delivery. The duration of insulin action may vary with injection site, blood flow, temperature, level of physical activity, etc. In the Diabetes Control and Complications Trial (DCCT)[1658] patients 13ï¿½39 years of age with Type I DM were studied. Those receiving "intensive" therapy (3 or more injections per day or use of an insulin pump) had approximately a 60% reduction in the incidence of retinopathy, nephropathy, and neuropathy compared to "conventional" (2 injections/day) dosing, but had a greater risk of serious hypoglycemia. Reanalysis of the data from this trial suggests that "moderate" glycemic control (HbA1c 2% or less above normal) is as beneficial as "tight" control in reducing diabetic complications while reducing risk of severe hypoglycemia.[1658] ï¿½Regular insulin (e.g., Humulinï¿½ R, Novolinï¿½ R), Insulin Aspart (NovoLogï¿½), or Insulin Lispro (Humalogï¿½): Subcutaneous dosage: Adults and children: The total daily dose is given as 2ï¿½4 injections per day. In general, insulin lispro and insulin aspart are equipotent to regular insulin, but with more rapid activity and a shorter duration of action when given SC. Always administer insulin aspart or insulin lispro just prior to the start of a meal to avoid hypoglycemia (see Administration). Regular insulin is typically administered 30 minutes before meals, or as a sliding scale based on blood sugar monitoring several times per day. Alternatively, controlled subcutaneous insulin infusion devices (CSIIs) may be used to deliver insulin lispro or regular human insulin (consult specialized references); therapy is provided by a professional team trained in CSIIs therapy and capable of supporting patient care continuously (i.e., 24-hours/7 days-a-week). ï¿½NPH or Lente insulin: Subcutaneous dosage: Adults: The total daily dose is given as 1ï¿½2 injections per day, given 30ï¿½60 minutes before a meal. Many patients are initially given a single daily dose 30ï¿½60 minutes before breakfast, but 24-h blood glucose control may not be possible with this regimen. Thus, a second injection 30ï¿½60 minutes before dinner or at bedtime may be required. When a sulfonylurea is used concomitantly in Type II DM, a low initial dose of NPH insulin (e.g., 10ï¿½15 units) is often given in the evening. In Type I DM, NPH insulin is frequently mixed with a short-acting insulin and given twice daily (see "split-mixed therapy"). The excess zinc in lente insulin can blunt the action of regular insulin when the two are mixed; therefore, NPH is preferred when an intermediate-acting and a short-acting insulin are combined in the same syringe. ï¿½Split-mixed therapy (i.e., intermediate-acting NPH or Lente insulin brands administered in combination with a short-acting insulin, like regular, aspart or lispro insulin): Subcutaneous dosage: Adults: A common regimen is to give NPH and a short-acting insulin (e.g., insulin aspart, lispro, or regular) concomitantly and give two injections per day. About 2/3 of the daily insulin dose is given before breakfast and about 1/3 is given before the evening meal. Initially, an intermediate-to-regular insulin ratio of 2:1 can be given 30ï¿½60 minutes before breakfast and an intermediate-to-regular insulin ratio of 1:1 can be given 30ï¿½60 minutes before dinner. The dosage and/or ratio can be adjusted, if necessary, based on the patient's blood glucose. If human aspart insulin is given as the short-acting insulin, administer 5ï¿½10 minutes prior to the meal. If human lispro is given as the short-acting insulin, administer 15 minutes prior to the meal. Another common regimen is to administer both a short-acting and intermediate-acting insulin before breakfast (e.g., regular with NPH), a short-acting insulin before dinner, and an intermediate-acting (e.g., NPH) insulin alone at bedtime. Additional regimens include regular, aspart, or lispro insulin at each meal and a dose of NPH or Lente insulin at supper or bedtime. ï¿½Premixed insulin lispro protamine/insulin lispro combinations (i.e., Humalogï¿½ Mixï¿½): Subcutaneous dosage: Adults: Premixed insulin lispro protamine/human lispro can be used when a intermediate-acting and short-acting insulin combination is desired. See "split-mixed" therapy. SC dosages are generally given 15 minutes before a meal. ï¿½Premixed human NPH/regular human insulin combinations (e.g., Humulinï¿½ 70/30 or 50/50 or Novolinï¿½ 70/30 or 50/50): Subcutaneous dosage (various brands): Adults: Premixed insulins can be used when a combination of intermediate-acting and short-acting insulin is desired. See "split-mixed" therapy. SC dosages are generally given 30ï¿½60 minutes before a meal. ï¿½Insulin glargine (i.e., Lantusï¿½): Subcutaneous dosage (Lantusï¿½ only): Adults: A single daily dose is given SC at bedtime, to provide the patient's basal insulin needs. If necessary, supplement with regular insulin or insulin lispro before meals to control post-prandial glucose. In clinical studies, when patients were transferred from once-daily NPH or Ultralente human insulin to once-daily insulin glargine, the initial dose was usually not changed. However, when patients were transferred from twice-daily NPH human insulin to insulin glargine once daily at bedtime, to reduce risk of hypoglycemia, the initial insulin glargine dose is reduced by approximately 20% (compared to total daily units of NPH human insulin) during the 1st week of insulin glargine tx and adjusted to response. ï¿½Ultralente insulins: Subcutaneous dosage: Adults: A single daily dose may be given 30ï¿½60 minutes before the AM or before the PM meal; or alternatively, the daily dose is divided and administered with both AM and PM meals to provide a more constant level of basal insulin. ï¿½Combining long-acting Ultralente insulin with regular insulin: Subcutaneous dosage: Adults: A common regimen is to give an animal source Ultralente insulin once daily with either the AM or the PM meal in addition to administration of a short-acting insulin before each meal. If human ultralente is used, it must be divided and given with both the AM and PM meals to provide a more constant level of basal insulin. For the treatment of gestational diabetes or for the treatment of patients with pre-existing diabetes mellitus (Type I or II) who are now pregnant: ï¿½for pregnant patients with gestational-onset diabetes not controlled by diet-therapy alone: Subcutaneous dosage (human regular and NPH insulin combination therapy): Adults (pregnant females): Dosage guidelines are variable and must be individualized. Initial suggested daily insulin requirements are roughly 0.3ï¿½0.7 units/kg/day; requirements usually increase during the second and third trimesters (i.e., 0.8 units/kg/day or more). The daily dose is usually divided in 2ï¿½3 doses and administered in varying ratios of NPH: regular insulin. Intensive therapy (> 3 daily injections) is rarely needed. Dose adjustments are based on fasting and postprandial blood glucose level. Per goals defined in ADA or ACOG guidelines, typical 2-hour postprandial glucose goals are <= 120 mg/dl. To prevent fetal and maternal complications, meticulous blood glucose control and monitoring is required. During labor, insulin requirements decrease and usually return to normoglycemia several days postpartum. Insulin is often discontinued during or after labor; monitor blood glucose during labor and the days postpartum; follow-up at 6 weeks postpartum. ï¿½for the treatment of pregnant patients with preexisting diabetes prior to pregnancy: Subcutaneous dosage (human regular and NPH insulin combination therapy): Adults (pregnant females): While initial suggested daily insulin requirements are roughly 0.5ï¿½0.7 units/kg of IBW/day in the 1st trimester; insulin needs may initially be lower than prepregnancy levels; individualize dosage. Daily requirements are higher in the 2nd and 3rd trimesters; roughly 0.6ï¿½0.8 units/kg (second trimester), and 0.9ï¿½1 units/kg (third trimester). The daily dose is usually divided in 2ï¿½3 doses and administered in varying ratios of NPH: regular insulin, dependent on individual patient needs. Dose adjustments are based on fasting and postprandial blood glucose as per goals defined in ADA and ACOG guidelines. To prevent fetal and maternal complications, meticulous blood glucose control and monitoring is required. At the onset of labor, insulin requirements typically decrease but must be carefully monitored and adjusted. Due to increased insulin sensitivity, insulin is usually held immediately postpartum until the blood glucose is >= 180 mg/dl. Insulin is then reinitiated at <= 90% of prepregnancy levels. For the treatment of diabetic ketoacidosis: Intravenous dosage (regular insulin only): Adults: Use regular insulin only, do not use any other type of insulin intravenously. Initially, a 0.1ï¿½0.15 unit/kg IV bolus, followed by 0.1 unit/kg/hour IV by continuous infusion. Additionally, adequate fluid therapy must be initiated (usually 0.45% or 0.9% NaCl infusion, fluid type and hourly requirements based on estimated patient need and serum osmolality). Blood glucose levels are checked hourly and the insulin infusion rate is adjusted accordingly. The insulin infusion should cause blood glucose to fall at a rate of about 80ï¿½100 mg/dl/hr; faster lowering of blood sugar can result in adverse effects, like cerebral edema. When the blood glucose falls to 250 mg/dl or less, the insulin infusion rate is usually halved and fluid therapy is changed to a dextrose 5%-containing fluid infusion; both are adjusted to maintain a blood glucose roughly 200ï¿½250 mg/dl until the acidosis is corrected. Children: Use regular insulin only, do not use any other type of insulin intravenously. Initially, 0.1 unit/kg IV bolus, followed by 0.1 unit/kg/hour (range: 0.05ï¿½0.2 units/kg/hr) continuous IV infusion. Additionally, adequate fluid therapy is initiated (usually 0.45% or 0.9% NaCl infusion, fluid type and hourly requirements based on estimated patient need and serum osmolality). Blood glucose levels are checked hourly and the insulin infusion rate is adjusted accordingly. Blood glucose levels are checked hourly and the insulin infusion rate is adjusted accordingly. The insulin infusion should cause blood glucose to fall at a rate of about 80ï¿½100 mg/dl/hr; faster lowering of blood sugar can result in adverse effects, like cerebral edema. When the blood glucose falls to 250 mg/dl or less, the insulin infusion rate is usually halved and fluid therapy is changed to a dextrose 5%-containing fluid infusion; both are adjusted to maintain a blood glucose roughly 200ï¿½250 mg/dl until the acidosis is corrected. For the treatment of hyperglycemic hyperosmolar nonketotic coma (HHNC) in patients with Type II diabetes mellitus: Intravenous dosage (regular insulin only): Adults: Use regular insulin only, do not use any other type of insulin IV. HHNC is a serious, acute complication of Type II diabetes mellitus. Give insulin IV unless severe complications (hypotension or significant hypokalemia) present. Generally, a low-dose is initiated with a bolus dose of 0.1 unit/kg IV, followed by a continuous infusion of 0.1 unit/kg/hr IV. Monitor blood sugars hourly and adjust infusion rate and fluids as indicated, continue until the blood glucose falls to 250 mg/dl. For nutritional supplementationï¿½ to maintain normoglycemia in very low birthweight infants with persistent glucose intolerance, including those neonates on parenteral nutrition with persistent glucose intolerance: Intravenous dosage (human regular insulin only): Neonates of very low birth weight with persistent glucose intolerance: Neonatal texts recommend a dosage of 0.01ï¿½0.1 units/kg/hour of regular insulin IV via continuous infusion (using infusion pump) Use regular insulin only, do not use any other type of insulin IV. NOTE: Neonates are especially sensitive to insulin, and a insulin regimen may rapidly induce hypoglycemia. Start at the lower end of the dosage range and monitor blood sugar and other parameters extremely closely. Blood sugar should be obtained every 15ï¿½30 minutes after initiation of the infusion, and after any change in infusion rate. Subcutaneous dosage (human regular insulin only): Neonates of very low birth weight with persistent glucose intolerance: Initially, 0.1ï¿½0.2 units/kg/dose SC of regular insulin administered every 6ï¿½12 hours; individualize subsequent doses. NOTE: Neonates are especially sensitive to insulin, and a insulin regimen may rapidly induce hypoglycemia. Start at the lower end of the dosage range and monitor blood sugar and other parameters extremely closely. Blood sugar should be obtained every 15ï¿½30 minutes after the initiation of treatment, and after any change in SC dosage. For the treatment of hyperkalemia: Intravenous dosage (regular insulin only): Adults: 5ï¿½10 units regular insulin infused IV and co-administered with 50 ml of D50W IV over 5 minutes. Use regular insulin only, do not use any other type of insulin intravenously. Subcutaneous dosage: Adults: 25 units regular insulin SC, co-administered with an infusion of D10W and sodium bicarbonate. Maximum Dosage Limits: Specific maximum dosage information is not available. Individualize dosage based on careful monitoring of blood glucose and other clinical parameters in all patient populations. Patients with hepatic impairment: Dosage should be modified depending on clinical response and degree of hepatic impairment, but no quantitative recommendations are available. Some studies have noted increased circulating levels of insulin in patients with hepatic failure. Individualize dosage based on blood glucose and other clinical parameters. Patients with renal impairment: The pharmacokinetics of insulin are generally unchanged with renal impairment, however, pharmacodynamic differences in the sensitivity of patients to insulin as renal function declines, resulting in increased responses to a given dosage. Individualize dosage based on blood glucose and other clinical parameters. The following represents rough guidelines for the dosage adjustment of either regular insulin or insulin lispro: CrCl 10ï¿½50 ml/min: administer 75% of recommended dose. CrCl < 10 ml/min: administer 25ï¿½50% of recommended dose and monitor blood glucose carefully.

Administration NOTE: Various types of insulin are available for subcutaneous administration, differing in the onset of action, peak effect, and duration of action. They are classified as short-acting (insulin aspart, insulin lispro, regular, semilente), intermediate-acting (insulin lispro protamine, NPH, lente), and long-acting (insulin glargine, ultralente, PZI) insulins. In many cases, more than one type of insulin preparation is administered in order to achieve the desired clinical effect. Dosage must be individualized; fasting or preprandial blood glucose concentrations of 80ï¿½120 mg/dl or an HbA1C of < 7 are desired in adults and adolescents; (children < 5 years, 100ï¿½200 mg/dl). Subcutaneous Administration ï¿½Most insulins are administered by subcutaneous injection only. Never administer any insulin except unbuffered regular-insulin intravenously. ï¿½Regular insulin is administered 30 minutes before meals. ï¿½Insulin lispro or any insulin mixtures containing insulin lispro are given within 15 minutes prior to the start of a meal. ï¿½Insulin aspart or any insulin mixtures containing insulin aspart are given within 5ï¿½10 minutes prior to the start of a meal. ï¿½Intermediate-acting (e.g., NPH or Lente) or long-acting (e.g., ultralente) insulins are usually administered 30ï¿½60 minutes before a meal or at bedtime. ï¿½Insulin glargine, a long-acting insulin analog, is usually administered once-daily prior to bedtime. Subcutaneous dosage preparation: ï¿½ONLY use insulin syringes marked in insulin units. There may be differences in the way units are indicated, depending on the size of the syringe and the manufacturer. Insulin syringes are manufactured with 0.25 ml, 0.3 ml, 0.5 ml, and 1-ml capacity. Two lengths of needles are available: short (8 mm) and long (12.7 mm). The short needles are not indicated for obese patients. ï¿½Before withdrawing a dose, rotate vial between the palms to mix; do not shake. If insulins are mixed together, draw the short-acting insulin (e.g., regular, aspart, or lispro only) into the syringe first to prevent clouding of the short-acting insulin by the longer-acting insulin. ï¿½NPH and regular insulin can be combined in the same syringe and be refrigerated for up to 3 weeks without changes in potency. Check manufacturer specifications for storage of other insulin products. ï¿½Do NOT mix the following intermediate and long-acting insulins with any other insulins or other solutions: Lente, Ultralente, PZI, or insulin glargine. A clinically significant interaction occurs when these insulins and regular insulin are mixed; zinc in these insulin solutions binds with regular insulin, changes in the onset and duration of insulin action could result. ï¿½Insulin pen/cartridge injector devices: If using a insulin pen-type injector, make sure the insulins are well-mixed prior to each injection to ensure uniform distribution of the insulin within the insulin cartridge. Tip and roll the pen prior to each use to ensure proper mixing technique. Do not shake. ï¿½Controlled subcutaneous insulin infusion devices (CSIIs): only the following insulins (regular insulin, insulin lispro) should be used in these devices. ï¿½Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use injections which are unusually viscous, cloudy, or discolored. Subcutaneous (SC) intermittent injection administration: ï¿½SC injections are usually made into the anterior and lateral aspects of the thigh, the upper arms, buttocks, or the abdomen. ï¿½Double-check dosage in syringe prior to administration. ï¿½Aspirate prior to injection to avoid injection into a blood vessel. Inject over 2ï¿½4 seconds. ï¿½Rotate administration sites with each injection to prevent lipodystrophy. However, staying within the same area (e.g., abdomen) is generally recommended to decrease the variability in insulin absorption from dose to dose. Intramuscular or Intravenous Administration ï¿½NOTE: Only regular, unbuffered insulin may be administered intravenously or intramuscularly. ï¿½Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use injections which are unusually viscous, cloudy, or discolored. Intramuscular (IM) injection: ï¿½Only regular, unbuffered insulin may be administered intramuscularly. ï¿½This route of administration is not commonly used or recommended. ï¿½Inject into a large muscle. Aspirate prior to injection to avoid injection into a blood vessel. Direct IV injection: ï¿½Only regular, unbuffered insulin may be administered IV. ï¿½Inject desired dose of undiluted regular insulin directly into a vein or via Y-site injection or 3-way stopcock at a rate of up to 50 units/minute. Continuous IV infusion: ï¿½Only regular, unbuffered insulin may be administered IV. ï¿½The concentration of insulin may be decreased by at least 20ï¿½80% due to adsorption to the plastic or glass container or tubing. ï¿½Dilute desired amount of regular insulin in any commonly used infusion solution. ï¿½An infusion may be prepared by adding 100 units of regular insulin to 100 ml of 0.9% NaCl or other compatible IV fluid (e.g., parenteral dextrose solutions); an initial infusion rate of 0.1 unit/kg/hr is frequently recommended, but must be individualized.

Contraindications Changes in insulin products should be made by experienced medical personnel. Changes in insulin species source (i.e., animal versus human, etc.), purity, or brand can necessitate dosage adjustments. The physiologic response resulting from the mixing of different insulins for subcutaneous administration together may differ from the response occurring when the insulins are administered separately. Treatment must be individualized. Diabetic patients must follow a regular, prescribed diet and exercise schedule to avoid either hypo- or hyperglycemia. The timing of meals and exercise with insulin doses is extremely important, and should remain consistent, unless prescribed otherwise. Fever, thyroid disease, infection, recent trauma or surgery, diarrhea secondary to malabsorption, vomiting, and certain medications can also affect insulin requirements, requiring dosage adjustments. Diabetic patients should be given a "sick-day" plan to take appropriate action with blood glucose monitoring and insulin therapy when acute illness is present. Hepatic disease, renal impairment, or renal failure may affect insulin dosage requirements. Some pharmacokinetic studies have shown increased circulating levels of insulin in patients with hepatic or renal failure. Insulin dosage adjustments may be needed in some patients. Regular insulin is the only formulation appropriate for intravenous administration (IV). Only regular insulin should be used in patients with diabetic ketoacidosis or diabetic coma. Intermediate or long-acting insulin preparations should not be used in the case of diabetic ketoacidosis (DKA) or other emergencies requiring rapid onset of insulin action. Regular insulin is also preferred for in those with poor tissue perfusion, shock, or cardiovascular collapse, or in patients requiring insulin for the treatment of hyperkalemia. All other preparations of insulin are contraindicated for these conditions, and they should not be administered intravenously. Only rapid-acting insulins (e.g., regular insulin, insulin lispro) should be used in controlled subcutaneous insulin infusion devices (CSIIs). Should mild to moderate hypoglycemia occur, the patient and patient's family should be instructed on how to recognize and manage the symptoms. In patients who are currently taking an alpha-glucosidase inhibitor (i.e., acarbose or miglitol) along with their insulin, oral glucose (dextrose) should be used to treat hypoglycemia; sucrose (table sugar) is unsuitable. Patients should be aware of the need to have a readily available source of glucose (dextrose, d-glucose) or other carbohydrate to treat hypoglycemic episodes. In severe hypoglycemia, intravenous dextrose or glucagon injections may be needed. Insulin injections should not be used by the family to treat those patients who are unconscious. Insulins are contraindicated for use in patients hypersensitive to the insulin or the excipients in the formulations. Minor, local, sensitivity on injection does not usually contraindicate therapy. In general, beef insulin should not be used in patients with a history of bovine protein hypersensitivity unless these patients have been adequately desensitized. Beef insulin and beef-pork insulin combinations are no longer available in the US due to concerns over the transmission of bovine spongiform encephalopathy (i.e., "mad-cow disease"). Under certain registration processes with the FDA, beef insulin may be imported by individuals from outside the US, but this approach is not recommended. Pork insulins are still available in the US; porcine insulins should not be used in patients with a history of porcine protein hypersensitivity unless these patients have been adequately desensitized. Insulins are classified in FDA pregnancy risk category B. There have been no fetal abnormalities reported in animal studies of this drug. Most experts recommend human regular insulin as the therapy of choice to maintain blood glucose as close to normal as possible during pregnancy in patients with Type I or II diabetes mellitus, and, if diet therapy alone is not successful, for those patients with gestational diabetes. In general, insulin requirements decline during the first trimester and increase during the second and third trimesters. Careful monitoring of the patient on insulin is required throughout pregnancy. Optimizing glycemic control before conception and during pregnancy appears to improve fetal outcome; this should include the avoidance of episodes of hypoglycemia. During the perinatal period, careful monitoring of neonates born to mothers with diabetes is recommended. Insulin is not excreted into breast milk. Breast-feeding, however, may decrease insulin requirements, despite the need for increased caloric intake. Women on insulin therapy should be encouraged to breast-feed their infants if no other contraindications to breast-feeding exist. However, careful observation of increased maternal caloric needs and maternal blood glucose levels are needed. Treatment of children and infants on insulin therapy requires special care. In general, special attention must be given to caloric intake, insulin dosage adjustments, and avoidance of low blood sugar. Insulin lispro (i.e., Humalogï¿½) is not currently approved for children under the age of 12 years, but clinical use of insulin lispro has been reported for both SC intermittent injections and use in controlled subcutaneous insulin infusion devices (CSIIs) in carefully selected and educated children. No long-term treatment data are available at this time.

Interactions Insulin has been administered along with other antidiabetic agents for the treatment of Type II diabetes mellitus not well-controlled on single agents. However, the risk of hypoglycemia may increase with such combinations. The hypoglycemic effect of insulin can be enhanced by the concomitant administration of alpha-glucosidase inhibitors, metformin, or oral sulfonylureas. Ethanol, guanethidine, and disopyramide can enhance the hypoglycemic effect of insulin, so dosage adjustments may be required. Serum glucose should be monitored closely when MAOIs are added to any regimen containing antidiabetic agents. Animal data indicate that MAOIs may stimulate insulin secretion. Inhibitors of MAO type A have been shown to prolong the hypoglycemic response to insulin and oral sulfonylureas. The phenothiazines, especially chlorpromazine, may increase blood sugar. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when any of these drugs are instituted. Carbonic anhydrase inhibitors can cause glycosuria and hyperglycemia in diabetic patients, thereby decreasing the effects of insulin therapy. Dosage adjustments may be required. Phenytoin, dextrothyroxine, glucagon, corticosteroids and corticotropin, ACTH, thyroid agents, thiazide diuretics, and triamterene can decrease the hypoglycemic effects of insulin by producing an increase in blood glucose levels. Patients receiving insulin should be closely monitored for signs indicating loss of diabetic control when therapy with any of these other agents is instituted. In addition, patients receiving insulin should be closely monitored for signs of hypoglycemia when therapy with any of these other agents is discontinued. beta-blockers exert complex actions on the body's ability to regulate blood glucose. Because of this, beta-blockers may cause a pharmacodynamic interaction with antidiabetic agents. beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Also, beta-blockers can blunt the tachycardic response to and exaggerate the hypertensive response to hypoglycemia. Although no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, patients receiving beta-blockers and antidiabetic agents concomitantly should be closely monitored for an inappropriate response. Selective beta-blockers, such as acebutolol, atenolol, or metoprolol, can cause fewer problems with blood glucose regulation, although these agents can still mask the symptoms of hypoglycemia. Diazoxide increases blood sugar by inhibiting insulin release from the pancreas and/or by stimulating the release of catecholamines, which in turn stimulate glycogenolysis. Thus, diazoxide and insulin are pharmacologic opposites. The hyperglycemic action of diazoxide can be diminished in patients receiving insulin, and, conversely, the dosage of insulin may need to be adjusted when diazoxide is added to the regimen. Changes in dietary intake and weight loss induced by orlistat may improve metabolic control in diabetic patients. A statistically significant number of obese, type 2 diabetics stabilized on sulfonylureas who received orlistat during a one-year double-blind, placebo-controlled study required a reduction in dose or discontinuation of drug therapy compared to the placebo group.[2261] Lower blood glucose may necessitate a dosage reduction of antidiabetic agents. Thyroid hormones are important in the regulation of carbohydrate metabolism, gluconeogenesis, the mobilization of glycogen stores, and protein synthesis. Close monitoring of blood glucose is necessary for individuals who use insulin or oral hypoglycemics whenever there is a change in thyroid treatment. It may be necessary to adjust the dose of antidiabetic agents if thyroid hormones are added or discontinued. Because garlic, Allium sativum increases blood insulin levels, the risk of hypoglycemia may be increased for individuals receiving antidiabetic agents. Additional monitoring may be required. Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood sugar. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. Chromium, as part of the glucose tolerance factor (GTF) molecule, appears to facilitate the binding of insulin to insulin receptors in tissues and to aide in glucose metabolism. Because blood glucose may be lowered by the use of chromium, patients who are on antidiabetic agents (e.g., insulin, metformin. sulfonylureas, thiazolidinediones, etc.) may need dose adjustments. Close monitoring of blood glucose is recommended. Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when quinolones and antidiabetic agents are coadministered. Bexarotene may enhance the hypoglycemic action of insulin. Patients should be closely monitored while receiving bexarotene in combination with insulin. Horse chestnut, Aesculus hippocastanum may interact with antidiabetic agents by enhancing hypoglycemic activity. The mechanism of this effect is not certain; clinical documentation of interactions is lacking at this time. Black cohosh, Cimicifuga racemosa, is reported to potentiate the effects of hypoglycemic medications based on the results of limited animal studies. Use caution when adding black cohosh to antidiabetic agents. Close serum glucose monitoring may be needed during initiation of treatment. Clinical documentation of an interaction in humans is lacking. Niacin (nicotinic acid) interferes with glucose metabolism and can result in hyperglycemia; monitor patients on antidiabetic agents for loss of blood glucose control if niacin therapy is added. Pentamidine can be harmful to pancreatic cells. This effect may lead to hypoglycemia acutely, followed hyperglycemia with prolonged pentamidine therapy. Patients on antidiabetic agents should be monitored for the need for dosage adjustments during the use of pentamidine. Administration of octreotide to patients receiving oral antidiabetic agents or insulin can produce hypoglycemia due to slowing of gut motility which leads to decreased postprandial glucose concentrations. Patients should be monitored closely and doses of these medications adjusted accordingly if octreotide is added. Pseudoephedrine and other sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications like the amphetamines may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. As long as blood glucose is carefully monitored to avoid hypoglycemia or hyperglycemia, it appears that adrenergic agents can be used concurrently. Dexfenfluramine or fenfluramine may also potentiate the actions of some antidiabetic agents via similar mechanisms on muscle glucose utilization. Estrogens, progestins, or oral contraceptives can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 ï¿½g of ethinyl estradiol per day. The presence or abscence of a concomitant progestin may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for changes in diabetic control when hormone therapy is instituted or discontinued. Administration of anabolic steroids or androgens to diabetic patients receiving antidiabetic agents can increase the risk of developing hypoglycemia; androgens have effects on carbohydrate metabolism and may decrease fasting blood glucose levels. Interestingly, this blood glucose-lowering effect is not observed in nondiabetic patients. Monitor closely for evidence of hypoglycemia if androgens are administered concomitantly with insulin.

Adverse Reactions Diabetic patients who have brittle diabetes, have received an overdose of insulin, have a delayed or decreased food intake, or undergo an excessive amount of exercise relative to their usual insulin dose can develop hyperinsulism, resulting in hypoglycemia. Hypoglycemia also has been reported in patients who were switched from beef to pork insulin preparations. Diabetic patients who develop adrenocortical insufficiency or Addison's disease may require decreased amounts of insulin. Hypoglycemia is manifested as hunger, pallor, nausea/vomiting, fatigue, perspiration, headache, palpitations, numbness of the mouth, tingling in the fingers, tremors, muscle weakness, blurred vision, hypothermia, uncontrolled yawning, irritability, mental confusion, sinus tachycardia, shallow breathing, and loss of consciousness. Hyperinsulism can cause aphasia, manic behavior, or other mental status changes. Prolonged hypoglycemia can result in irreversible brain damage. Patients who receive overdoses of insulin can experience a hyperglycemic rebound reaction (Somogyi effect). Hypoglycemia induces an accelerated release of glucagon, adrenal corticosteroids, and growth hormone, which act to antagonize the effects of insulin, causing hyperglycemia. Insulin dosages must be reduced in these patients and blood glucose monitored closely. Because insulin facilitates the intracellular uptake of potassium, hypokalemia is also possible. During insulin therapy, injection site reactions can occur, manifested as lipohypertrophy (the accumulation of SC fat around a site of injection that has been used repeatedly) and lipoatrophy (the breakdown of adipose tissue at the insulin injection site, causing a depression in the skin). These lipodystrophy reactions can be avoided by rotating the sites of injection so that a site is not used more than once every 1ï¿½2 months. Injection site reactions that are allergic in nature can also occur, resulting in pruritus, burning and swelling at the injection site. Generalized urticaria and anaphylactoid reactions can rarely occur with insulin therapy. Human insulin appears to be the least allergenic, but may also cause reactions. Desensitization procedures may be necessary in some patients. Insulin resistance occasionally can develop in patients requiring daily insulin injections. It can represent an acute resistance, often due to infections, surgical trauma, emotional disturbances, or other endocrine disorders; or chronic insulin resistance, which is most likely due to increased levels of circulating insulin antibodies. Hyperglycemia resulting from apparrent chronic insulin resistance may be treated by changing the insulin source to a less antigenic product (e.g., pork or human). The clinical significance of antibody formation to various insulin products is not always clear, as some human insulin analogs may also cause antibody formation. Corticosteroids have been used if changing to a different insulin species source is not effective.

1658. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977ï¿½86.