Insulin Lispro

Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.

Humalog differs from Regular human insulin by its rapid onset of action as well as a shorter duration of activity. Therefore, the dose of Humalog Mix50/50 should be given within 15 minutes before a meal.

Hypoglycemia is the most common adverse effect associated with the use of insulins, including Humalog Mix50/50. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose monitoring is recommended for all patientswith 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.

Fluid retention and heart failure with concomitant use of PPAR-gamma agonists

Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)gamma agonists, can cause dose-related fluid retention, particularly when used in combinationwith insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including Humalog Mix50/50, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to currentstandards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.

Serious side effects have been reported with Insulin Lispro including the following:

Low blood sugar (hypoglycemia). Low blood sugar can occur with changes in insulin regimens or dose miscalculations. Monitor blood glucose levels regularly. Signs and symptoms of low blood sugar include:

• sweating
• dizziness or lightheadedness
• shakiness
• hunger
• fast heart beat
• tingling of lips and tongue
• trouble concentrating or confusion
• blurred vision
• slurred speech
• anxiety, irritability or mood changes
• headache
• Insulin Lispro may also cause the following side effects. Tell your doctor right away if you experience any of the following signs and symptoms:
• rash and itching
• difficulty breathing
• hives
• wheezing
• fast heartbeat
• sweating
• weakness
• muscle cramps
• abnormal heartbeat
• shortness of breath
• large weight gain in a short period of time
• swelling of the arms, hands, feet, ankles, or lower legs

Insulin Lispro can cause low blood sugar, which can cause dizziness and drowsiness. Do not drive or operate heavy machinery until you know how Insulin Lispro affects you.

Do not take Insulin Lispro if you:

are allergic to Insulin Lispro or to any of its ingredients

have low blood sugar

Never share an injection pen, cartridge, or syringe with another person, even if the needle has been changed.

You should not use insulin lispro if you are allergic to it, or if you are having an episode of hypoglycemia (low blood sugar).

Insulin lispro should not be given to a child younger than 3 years old. Insulin lispro should not be used to treat type 2 diabetes in a child of any age.

To make sure insulin lispro is safe for you, tell your doctor if you have:

• liver or kidney disease; or

• low levels of potassium in your blood (hypokalemia).

Tell your doctor if you also take pioglitazone or rosiglitazone (sometimes contained in combinations with glimepiride or metformin). Taking certain oral diabetes medicines while you are using insulin may increase your risk of serious heart problems.

Follow your doctor's instructions about using insulin if you are pregnant or breast-feeding a baby. Blood sugar control is very important during pregnancy, and your dose needs may be different during each trimester of pregnancy. Your dose needs may also be different while you are breast-feeding.

Since insulin lispro is used before meals, you may not be on a timed dosing schedule. Whenever you use insulin lispro, be sure to eat a meal within 15 minutes. Do not use extra insulin lispro to make up a missed dose.

Keep insulin on hand at all times. Get your prescription refilled before you run out of medicine completely.

Many other medicines can affect your blood sugar, and some medicines can increase or decrease the effects of insulin. Some drugs can also cause you to have fewer symptoms of hypoglycemia, making it harder to tell when your blood sugar is low. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using. This includes prescription and over-the-counter medicines, vitamins, and herbal products.

Specific Drugs

Absorption

Bioavailability

Following sub-Q administration, more rapidly absorbed than soluble preparations of insulin human or insulins of animal origin.1 2 3 6 9 10 51 73 144 145 165

Peak plasma insulin concentrations are higher and occur earlier with insulin lispro (at 30–90 minutes) than with insulin human (at 50–120 minutes).1 2 6 9 10 11 73 165

Following sub-Q administration of the fixed combination of insulin lispro and insulin lispro protamine (Humalog Mix 75/25), peak serum insulin concentrations were observed at 30–240 minutes (median: 60 minutes).165 More rapidly absorbed than the fixed combination of insulin human (regular) and isophane insulin human (Humulin 70/30).165

Onset

Many factors can affect the onset, degree, and duration of insulin activity (e.g., injection technique, presence of insulin antibodies, site of injection, tissue blood supply, temperature, excipients in insulin formulations, and interindividual and intraindividual differences in response).1 19 47 74 83

Following sub-Q injection of insulin lispro, onset generally ranges from 0.25–0.5 hours versus 0.5–1 hours for insulin human, respectively.1 3 9 51 73 74 83 Peak glycemic response for insulin lispro or insulin human occurs at 0.5–2.5 or 1–5 hours, respectively.1 3 9 51 73 74 83

Duration

Following sub-Q administration, the duration of hypoglycemic action of insulin lispro is 3–6.5 hours compared with 6–10 hours for insulin human.47 51 73 74 83

The duration of action of Humalog Mix 75/25 is similar to that of Humulin 70/30.165

Food

Administer 15 minutes before or immediately after meals.1 72

Special Populations

The presence of hepatic impairment does not affect the absorption in patients with type 2 diabetes mellitus.1

Distribution

Not known whether insulin lispro is distributed into human milk; however, other insulins (e.g., insulin human) are distributed into milk.1 Does not appear to cross the placenta in pregnant women with gestational diabetes.164

Extent

The volume of distribution of insulin lispro reportedly is identical to that of insulin human and ranges from 0.26–0.36 L/kg.1

Special Populations

Hepatic impairment does not affect the distribution in patients with type 2 diabetes mellitus.1

Elimination

Metabolic fate has not been determined in humans.1 165 In animals, metabolism of insulin lispro is identical to that of insulin human.1 165

Metabolism

Insulin is rapidly metabolized mainly in the liver and to a lesser extent in the kidneys and muscle tissue.d

Half-life

1 or 1.5 hours for insulin lispro or insulin human, respectively.2 51

Special Populations

Circulating insulin concentrations may be increased in patients with renal or hepatic failure.1

• Insulin, Rapid-Acting

Note: Insulin lispro is a rapid-acting insulin analog which is normally administered SubQ as a premeal component of the insulin regimen or as a continuous SubQ infusion and should be used with intermediate- or long-acting insulin. When compared to insulin regular, insulin lispro has a more rapid onset and shorter duration of activity. In carefully controlled clinical settings with close medical supervision and monitoring of blood glucose and potassium, insulin lispro U 100 (100 units/mL) may also be administered IV; insulin lispro U 200 (200 units/mL) may not be administered IV. Insulin requirements vary dramatically between patients and dictate frequent monitoring and close medical supervision.

Diabetes mellitus, type 1: SubQ:

General insulin dosing:

Type 1: Note: Multiple daily doses or continuous subcutaneous infusions guided by blood glucose monitoring are the standard of diabetes care. Combinations of insulin formulations are commonly used. The daily doses presented below are expressed as the total units/kg/day of all insulin formulations combined.

Initial total insulin dose: 0.2 to 0.6 units/kg/day in divided doses. Conservative initial doses of 0.2 to 0.4 units/kg/day are often recommended to avoid the potential for hypoglycemia. A rapid-acting insulin may be the only insulin formulation used initially.

Usual maintenance range: 0.5 to 1 units/kg/day in divided doses. An estimate of anticipated needs may be based on body weight and/or activity factors as follows:

Nonobese: 0.4 to 0.6 units/kg/day

Obese: 0.8 to 1.2 units/kg/day

Pubescent Children and Adolescents: During puberty, requirements may substantially increase to >1 unit/kg/day and in some cases up to 2 units/kg/day (IDF-ISPAD, 2011).

Division of daily insulin requirement (“conventional therapy”): Generally, 50% to 75% of the total daily dose (TDD) is given as an intermediate- or long-acting form of insulin (in 1 to 2 daily injections). The remaining portion of the TDD is then divided and administered before or at mealtimes (depending on the formulation) as a rapid-acting (eg, insulin aspart) or short-acting form of insulin. Some patients may benefit from the use of CSII which delivers rapid-acting insulin (insulin aspart) as a continuous infusion throughout the day and as boluses at mealtimes via an external pump device.

Division of daily insulin requirement (“intensive therapy”): Basal insulin delivery with 1 or 2 doses of intermediate- or long-acting insulin formulations superimposed with doses of short- or rapid-acting insulin (eg, insulin aspart) formulations 3 or more times daily.

Adjustment of dose: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Since combinations of agents are frequently used, dosage adjustment must address the individual component of the insulin regimen which most directly influences the blood glucose value in question, based on the known onset and duration of the insulin component. Treatment and monitoring regimens must be individualized. Also see Additional Information or Pharmacotherapy Pearls.

Continuous SubQ insulin infusion (insulin pump): A combination of a "basal" continuous insulin infusion rate with preprogrammed, premeal bolus doses which are patient controlled. When converting from multiple daily SubQ doses of maintenance insulin, it is advisable to reduce the basal rate to less than the equivalent of the total daily units of the longer acting insulin (eg, NPH); divide the total number of units by 24 to get the basal rate in units/hour. Do not include the total units of regular insulin or other rapid-acting insulin formulations in this calculation. The same premeal regular insulin dosage may be used.

Diabetes mellitus, type 2: SubQ:

General considerations for insulin use in type 2 diabetes:

Timing of initiation: The goal of therapy is to achieve an HbA1c <7%. According to a position statement by the ADA and European Association for the Study of Diabetes (EASD), dual therapy (metformin + a second antihyperglycemic agent) is recommended in patients with type 2 diabetes who fail to achieve glycemic goals after ~3 months with lifestyle interventions and metformin monotherapy (unless contraindications to metformin exist). Preference is not given for adding insulin or a noninsulin agent as the second antihyperglycemic agent (drug choice should be individualized based on patient characteristics). However, insulin should be considered as part of a combination regimen when hyperglycemia is severe, particularly if patient is symptomatic or has catabolic features (eg, weight loss, ketosis). If insulin is selected, the addition of basal insulin (ie, a long-acting insulin such as glargine or detemir [not insulin lispro]) is recommended. If HbA1c target not achieved after ~3 months of dual therapy, may proceed to triple therapy (Inzucchi, 2015).

Intensification of therapy: If HbA1c target has not been met, despite titrating basal insulin (ie, long-acting insulin) to provide acceptable fasting blood glucose concentrations, intensification of therapy should be considered to cover postprandial glucose excursions. Options include adding a GLP-1 receptor agonist (eg, exenatide, liraglutide) or adding a mealtime insulin (1 injection of a rapid-acting insulin analog [lispro, aspart, glulisine]) initiated at a dose of 4 units or 0.1 units/kg or 10% basal dose before largest meal; may progress to “basal-bolus” dosing of 3 injections of a rapid-acting insulin analog [lispro, aspart, glulisine] per meal or dose by adding up the total current insulin dose, and provide one-half of this amount as basal and one-half as mealtime insulin (split evenly between 3 meals). Alternatively, although less studied, may transition from basal insulin (ie, long-acting insulin) to a twice daily premixed (or biphasic) insulin analog (70/30 aspart mix, 75/25 or 50/50 lispro mix) (Inzucchi, 2015).

Diabetic ketoacidosis, mild-to-moderate (off-label use): SubQ: Initial: 0.3 units/kg, followed by 0.1 units/kg every hour until blood glucose <250 mg/dL, then decrease to 0.05 units/kg/hour until resolution of ketoacidosis (Umpierrez 2004). Also, refer to institution-specific protocols where appropriate.

Refer to indication-specific dosing for obesity-related information (may not be available for all indications).