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HUMALOG® Mix50/50TM
50% INSULIN LISPRO PROTAMINE
SUSPENSION AND
50% INSULIN LISPRO INJECTION
(rDNA ORIGIN)
100 UNITS PER ML (U-100)
DESCRIPTION
Humalog® Mix50/50™ [50% insulin lispro protamine suspension and 50% insulin lispro injection, (rDNA origin)] is a mixture of insulin lispro solution, a rapid–acting blood glucose–lowering agent and insulin lispro protamine suspension, an intermediate–acting blood glucose–lowering agent. Chemically, insulin lispro is Lys(B28), Pro(B29) human insulin analog, created when the amino acids at positions 28 and 29 on the insulin B–chain are reversed. Insulin lispro is synthesized in a special non–pathogenic laboratory strain of Escherichia coli bacteria that has been genetically altered to produce insulin lispro. Insulin lispro protamine suspension (NPL component) is a suspension of crystals produced from combining insulin lispro and protamine sulfate under appropriate conditions for crystal formation.
Insulin lispro has the following primary structure:
Insulin lispro has the empirical formula C257H383N65O77S6 and a molecular weight of 5808, both identical to that of human insulin.
Humalog Mix50/50 vials and Pens contain a sterile suspension of insulin lispro protamine suspension mixed with soluble insulin lispro for use as an injection.
Each milliliter of Humalog Mix50/50 injection contains insulin lispro 100 units, 0.19 mg protamine sulfate, 16 mg glycerin, 3.78 mg dibasic sodium phosphate, 2.20 mg Metacresol, zinc oxide span adjusted to provide 0.0305 mg zinc ion, 0.89 mg phenol, and Water for Injection. Humalog Mix50/50 has a pH of 7.0 to 7.8. Hydrochloric acid 10% and/or sodium hydroxide 10% may have been added to adjust pH.
CLINICAL PHARMACOLOGY
Antidiabetic Activity
The primary activity of insulin, including Humalog Mix50/50, 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.
Insulin lispro, the rapid–acting component of Humalog Mix50/50, has been shown to be equipotent to Regular 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.
Pharmacokinetics
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 early onset of activity of Humalog Mix50/50 is directly related to the rapid absorption of Humalog. The time course of action of insulin and insulin analogs, such as Humalog (and hence Humalog Mix50/50), may vary considerably in different individuals or within the same individual. The parameters of Humalog Mix50/50 activity (time of onset, peak time, and duration) as presented in Figures 2 and 3 should be considered only as general guidelines. 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 (see General under PRECAUTIONS).
In a glucose clamp study performed in 30 nondiabetic subjects, the onset of action and glucose–lowering activity of Humalog, Humalog Mix50/50, Humalog® Mix75/25™, and insulin lispro protamine suspension (NPL component) were compared (see Figure 2). Graphs of mean glucose infusion rate versus time showed a distinct insulin activity profile for each formulation. The rapid onset of glucose–lowering activity characteristic of Humalog was maintained in Humalog Mix50/50.
Direct comparison between Humalog Mix50/50 and Humulin 50/50 was not performed. However, a cross–study comparison shown on Figure 3 suggests that Humalog Mix50/50 has a duration of activity that is similar to Humulin 50/50.
Figures 2 and 3 represent insulin activity profiles as measured by glucose clamp studies in healthy nondiabetic subjects.
Figure 2 shows the time activity profiles of Humalog, Humalog Mix75/25, Humalog Mix50/50, and insulin lispro protamine suspension (NPL component).
Figure 3 is a comparison of the time activity profiles of Humalog Mix50/50 (see Figure 3a) and of Humulin 50/50 (see Figure 3b) from two different studies.
Special Populations
INDICATIONS AND USAGE
Humalog Mix50/50, a mixture of 50% insulin lispro protamine suspension and 50% insulin lispro injection, (rDNA origin), is indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia. Based on cross–study comparisons of the pharmacodynamics of Humalog Mix50/50 and Humulin 50/50, it is likely that Humalog Mix50/50 has a more rapid onset of glucose–lowering activity compared with Humulin 50/50 while having a similar duration of action. This profile is achieved by combining the rapid onset of Humalog with the intermediate action of insulin lispro protamine suspension.
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
General
Information for Patients
Laboratory Tests
Drug Interactions
Carcinogenesis, Mutagenesis, Impairment of Fertility
Pregnancy
Nursing Mothers
It is unknown whether insulin lispro is excreted in significant amounts in human milk. Many drugs, including human insulin, are excreted in human milk. For this reason, caution should be exercised when Humalog Mix50/50 is administered to a nursing woman. Patients with diabetes who are lactating may require adjustments in Humalog Mix50/50 dose, meal plan, or both.
Pediatric Use
Safety and effectiveness of Humalog Mix50/50 in patients less than 18 years of age have not been established.
Geriatric Use
Clinical studies of Humalog Mix50/50 did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should take into consideration the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this population.
ADVERSE REACTIONS
Clinical studies comparing Humalog Mix50/50 with human insulin mixtures did not demonstrate a difference in frequency of adverse events between the two treatments.
Adverse events commonly associated with human insulin therapy include the following:
Body as a Whole — allergic reactions (see PRECAUTIONS).
Skin and Appendages — injection site reaction, lipodystrophy, pruritus, rash.
Other — hypoglycemia (see WARNINGS and PRECAUTIONS).
OVERDOSAGE
Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure, or both. 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.
DOSAGE AND ADMINISTRATION
Insulin Products | Dose, U/kg | Time of Peak Activity, Hours After Dosing | Percent of Total Activity Occurring in the First 4 Hours |
Humalog | 0.3 | 2.4 | 70% |
Humulin R | 0.32 | 4.4 | 54% |
Humalog Mix75/25 | 0.3 | 2.6 | 35% |
Humulin 70/30 | 0.3 | 4.4 | 32% |
Humalog Mix50/50 | 0.3 | 2.3 | 45% |
Humulin 50/50 | 0.3 | 3.3 | 44% |
NPH | 0.32 | 5.5 | 14% |
NPL component | 0.3 | 5.8 | 22% |
Humalog Mix50/50 is intended only for subcutaneous administration. Humalog Mix50/50 should not be administered intravenously. Dosage regimens of Humalog Mix50/50 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. Humalog has been shown to be equipotent to Regular 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 quicker glucose–lowering effect of Humalog is related to the more rapid absorption rate of insulin lispro from subcutaneous tissue.
Direct comparison between Humalog Mix50/50 and Humulin 50/50 was not performed. However, a cross–study comparison shown in Figure 3 suggests that Humalog Mix50/50 has a duration of activity that is similar to Humulin 50/50.
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. As with all insulin preparations, the time course of action of Humalog Mix50/50 may vary considerably in different individuals or within the same individual. Patients must be educated to use proper injection techniques.
Humalog Mix50/50 should be inspected visually before use. Humalog Mix50/50 should be used only if it appears uniformly cloudy after mixing. Humalog Mix50/50 should not be used after its expiration date.
HOW SUPPLIED
Literature issued September 6, 2007
KwikPens manufactured by
Eli
Lilly and Company, Indianapolis, IN 46285, USA
Pens manufactured
by
Eli Lilly and Company, Indianapolis, IN 46285,
USA
Vials manufactured by
Eli
Lilly and Company, Indianapolis, IN 46285, USA or
Lilly France,
F-67640 Fegersheim, France
for Eli Lilly and
Company, Indianapolis, IN 46285, USA
www.humalog.com
Copyright © 2007, Eli Lilly and Company. All rights reserved.
Supplement Patient Material Section
Patient
Information
Humalog® (HU-ma-log)
Mix50/50TM
50% insulin lispro protamine
suspension and
50% insulin lispro injection (rDNA origin)
Important: Know your insulin. Do not change the type of insulin you use unless told to do so by your healthcare provider. Your insulin dose and the time you take your dose can change with different types of insulin. Make sure you have the right type and strength of insulin prescribed for you. |
Read the Patient Information that comes with Humalog Mix50/50 before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your diabetes or treatment. Make sure that you know how to manage your diabetes. Ask your healthcare provider if you have questions about managing your diabetes.
What is Humalog Mix50/50?
Humalog Mix50/50 is a mixture of fast-acting and longer-acting man-made insulins. Humalog Mix50/50 is used to control high blood sugar (glucose) in people with diabetes.
Humalog Mix50/50 comes in:
10 mL vials (bottles) for use with a syringe
Prefilled pens
Who should not take Humalog Mix50/50?
Do not take Humalog Mix50/50 if:
your blood sugar is too low (hypoglycemia). After treating your low blood sugar, follow your healthcare provider's instructions on the use of Humalog Mix50/50.
you are allergic to anything in Humalog Mix50/50. See the end of this leaflet for a complete ul of ingredients in Humalog Mix50/50.
Tell your healthcare provider:
about all your medical conditions. Medical conditions can affect your insulin needs and your dose of Humalog Mix50/50.
if you are pregnant or breastfeeding. You and your healthcare provider should talk about the best way to manage your diabetes while you are pregnant or breastfeeding. Humalog Mix50/50 has not been studied in pregnant or nursing women.
about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Many medicines can affect your blood sugar levels and insulin needs. Your Humalog Mix50/50 dose may need to change if you take other medicines.
Know the medicines you take. Keep a ul of your medicines with you to show to all of your healthcare providers.
How should I use Humalog Mix50/50?
Talk to your healthcare provider if you have any questions. Your healthcare provider will tell you the right syringes to use with Humalog Mix50/50 vials. Your healthcare provider should show you how to inject Humalog Mix50/50 before you start using it. Read the User Manual that comes with your Humalog Mix50/50 prefilled pen.
Use Humalog Mix50/50 exactly as prescribed by your healthcare provider.
Humalog Mix50/50 starts working faster than other insulins that contain regular human insulin. Inject Humalog Mix50/50 fifteen minutes or less before a meal. If you do not plan to eat within 15 minutes, delay the injection until the correct time (15 minutes before eating).
Check your blood sugar levels as told by your healthcare provider.
Mix Humalog Mix50/50 well before each use. For Humalog Mix50/50 in a vial, carefully shake or rotate the vial until completely mixed. For prefilled pens, carefully follow the User Manual for instructions on mixing the pen. Humalog Mix50/50 should be cloudy or milky after mixing well.
Look at your Humalog Mix50/50 before each injection. If it is not evenly mixed or has solid particles or clumps in it, do not use. Return it to your pharmacy for new Humalog Mix50/50.
Inject your dose of Humalog Mix50/50 under the skin of your stomach area, upper arm, upper leg, or buttocks. Never inject Humalog Mix50/50 into a muscle or vein.
Change (rotate) your injection site with each dose.
Your insulin needs may change because of:
illness
stress
other medicines you take
changes in eating
physical activity changes
Follow your healthcare provider's instructions to make changes in your insulin dose.
Never mix Humalog Mix50/50 in the same syringe with other insulin products.
Never use Humalog Mix50/50 in an insulin pump.
Always carry a quick source of sugar to treat low blood sugar, such as glucose tablets, hard candy, or juice.
What are the possible side effects of Humalog Mix50/50?
Low Blood Sugar (Hypoglycemia). Symptoms of low blood sugar include:
hunger
dizziness
feeling shaky or shakiness
lightheadedness
sweating
irritability
headache
fast heartbeat
confusion
Low blood sugar symptoms can happen suddenly. Symptoms of low blood sugar may be different for each person and may change from time to time. Severe low blood sugar can cause seizures and death. Low blood sugar may affect your ability to drive a car or use mechanical equipment, risking injury to yourself or others. Know your symptoms of low blood sugar. Low blood sugar can be treated by drinking juice or regular soda or eating glucose tablets, sugar, or hard candy. Follow your healthcare provider's instructions for treating low blood sugar. Talk to your healthcare provider if low blood sugar is a problem for you.
Serious allergic reactions (whole body allergic reaction). Severe, life-threatening allergic reactions can happen with insulin. Get medical help right away if you develop a rash over your whole body, have trouble breathing, wheezing, a fast heartbeat, or sweating.
Reactions at the injection site (local allergic reaction). You may get redness, swelling, and itching at the injection site. If you keep having injection site reactions or they are serious, you need to call your healthcare provider. Do not inject insulin into a skin area that is red, swollen, or itchy.
Skin thickens or pits at the injection site (lipodystrophy). This can happen if you don't change (rotate) your injection sites enough.
These are not all the side effects from Humalog Mix50/50. Ask your healthcare provider or pharmacist for more information.
How should I store Humalog Mix50/50?
Store all unopened (unused) Humalog Mix50/50 in the original carton in a refrigerator at 36°F to 46°F (2°C to 8°C). Do not freeze.
Do not use Humalog Mix50/50 that has been frozen.
Do not use after the expiration date printed on the carton and label.
Protect Humalog Mix50/50 from extreme heat, cold or light.
After starting use (open):
Vials: Keep in the refrigerator or at room temperature below 86°F (30°C) for up to 28 days. Keep open vials away from direct heat or light. Throw away an opened vial 28 days after first use, even if there is insulin left in the vial.
Prefilled Pens: Do not store a prefilled pen that you are using in the refrigerator. Keep at room temperature below 86°F (30°C) for up to 10 days. Throw away a prefilled pen 10 days after first use, even if there is insulin left in the pen.
General information about Humalog Mix50/50
Use Humalog Mix50/50 only to treat your diabetes. Do not share it with anyone else, even if they also have diabetes. It may harm them.
This leaflet summarized the most important information about Humalog Mix50/50. If you would like more information about Humalog Mix50/50 or diabetes, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Humalog Mix50/50 that is written for health professionals.
For questions you may call 1–800–LillyRx (1–800–545–5979) or visit www.humalog.com.
What are the ingredients in Humalog Mix50/50?
Active ingredients: insulin lispro protamine suspension and insulin lispro.
Inactive ingredients: protamine sulfate, glycerin, dibasic sodium phosphate, metacresol, zinc oxide (zinc ion), phenol and water for injection.
Patient Information issued September 6, 2007
KwikPens
manufactured by
Eli Lilly and Company, Indianapolis,
IN 46285, USA
Pens
manufactured by
Eli Lilly and Company, Indianapolis,
IN 46285, USA
Vials
manufactured by
Eli Lilly and Company, Indianapolis,
IN 46285, USA or
Lilly France, F-67640 Fegersheim, France
for
Eli Lilly and Company, Indianapolis, IN 46285, USA
www.humalog.com
Copyright © 2007, Eli Lilly and Company. All rights reserved.