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Combination Insulins     

Combination Insulins   top of page icon

Novolin® 70/30 - Humulin® 70/30 Novolog® Mix 70/30
Humalog® Mix 75/25  

Novolin® 70/30 - Humulin® 70/30    top of page icon

Onset
30-60 min
Peak:
2-12 hours
Duration:
18 - 24 hours
Solution
Cloudy
Comments: Mixture of 70% NPH, Human Insulin Isophane Suspension and 30% Regular, Human Insulin Injection.    Recommended interval between dosing and meal initiation: 30 minutes.
Mixing
You should not attempt to change the ratio of this product by adding additional NPH or Regular insulin to the vial. If the physician has prescribed insulin mixed in a proportion other than 70% NPH and 30% Regular, you should use the separate insulin formulations (e.g.  NPH and Regular insulin ) in the amounts recommended by the physician.

All Unopened Novolin 70/30:
• Keep all unopened Novolin 70/30 in the refrigerator between 36° to 46°F (2° to 8°C).
• Do not freeze. Do not use Novolin 70/30 if it has been frozen.
• If refrigeration is not possible, the unopened vial may be kept at room temperature for up to 6 weeks (42 days), as long as it is kept at or below 77°F (25°C).
• Keep unopened Novolin 70/30 in the carton to protect from light.


Novolin 70/30 in use:
Vials
• Keep at room temperature below 77°F (25°C) for up to 6 weeks (42 days).
• Keep vials away from direct heat or light.
• Throw away an opened vial after 6 weeks (42 days) of use, even if there is insulin left in the vial.
• Unopened vials can be used until the expiration date on the Novolin 70/30 label, if the medicine has been stored in a refrigerator.

Novolog® Mix 70/30    top of page icon

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Onset
10 - 20 minutes
Peak:
1-4 hours
Duration:
18 - 24 hours
Solution
Cloudy
Comments NovoLog® Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart injection) is a human insulin analog suspension containing 70% insulin aspart protamine crystals and 30% soluble insulin aspart.  Recommended interval between dosing and meal initiation: 10-20 minutes.
Mixing
Manufacturer:  NovoLog Mix 70/30 should not be mixed with any other insulin product.


INDICATIONS AND USAGE
NovoLog Mix 70/30 is an insulin analog indicated to improve glycemic control in patients with diabetes mellitus.
Important Limitations of Use: In premix insulins, such as Novolog Mix 70/30, the proportions of rapid acting and long acting insulins are fixed and do not allow for basal versus prandial dose adjustments.

CLINICAL PHARMACOLOGY


DOSAGE AND ADMINISTRATION
  • Only for subcutaneous injection
    Type 1 DM: dose within 15 minutes before meal initiation.
    Type 2 DM: dose within 15 minutes before or after starting a meal.
  • Do not administer intravenously.
  • Do not use in insulin infusion pumps.
  • Must be resuspended immediately before use.
  • Additional information

DOSAGE FORMS AND STRENGTHS
Each presentation contains 100 Units of insulin aspart per mL (U-100) (3)
   - 10 mL vials
   -  3 mL NovoLog Mix 70/30 FlexPen


CONTRAINDICATIONS
  • Do not use during episodes of hypoglycemia
  • Do not use in patients with hypersensitivity to NovoLog Mix 70/30 or one of its excipients

WARNINGS AND PRECAUTIONS
  • NovoLog Mix 70/30 should not be mixed with any other insulin product.
  • Hypoglycemia is the most common adverse effect of insulin therapy. Glucose monitoring is recommended for all patients with diabetes. Any change of insulin dose should be made cautiously and only under medical supervision.
  • Insulin, particularly when given in settings of poor glycemic control, can cause hypokalemia. Use caution in patients predisposed to hypokalemia.
  • Like all insulins, NovoLog Mix 70/30 requirements may be reduced in patients with renal impairment or hepatic impairment.
  • Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with insulin products, including NovoLog Mix 70/30.
  • Additional info
ADVERSE REACTIONS
Adverse reactions observed with insulin therapy include hypoglycemia, allergic reactions, local injection site reactions, lipodystrophy, rash and pruritus.
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch      Additional info.

DRUG INTERACTIONS
  • The following may increase the blood glucose lowering effect and susceptibility to hypoglycemia: oral antidiabetic products, pramlintide, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g. octreotide), sulfonamide antibiotics.
  • The following may reduce the blood-glucose-lowering effect: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives), atypical antipsychotics.
  • Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin.
  • Pentamidine may cause hypoglycemia, which may be followed by hyperglycemia.
  • The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic products such as beta-blockers, clonidine, guanethidine, and reserpine.

HOW SUPPLIED/STORAGE AND HANDLING 




DOSAGE AND ADMINISTRATION

Dosing
NovoLog Mix 70/30 is an insulin analog with an earlier onset and intermediate duration of action in comparison to the basal human insulin premix. The addition of protamine to the rapid-acting aspart insulin analog (NovoLog) results in insulin activity that is 30% short-acting and 70% long-acting. NovoLog Mix 70/30 is typically dosed on a twice-daily basis (with each dose intended to cover 2 meals or a meal and a snack). The dosage of NovoLog Mix 70/30 must be individualized. The written prescription for NovoLog Mix 70/30 should include the full name, to avoid confusion with NovoLog (insulin aspart) and Novolin 70/30 (human premix).

NovoLog Mix 70/30 should appear uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles. NovoLog Mix 70/30 should not be used after the printed expiration date.

NovoLog Mix 70/30 should be administered by subcutaneous injection in the abdominal region, buttocks, thigh, or upper arm. NovoLog Mix 70/30 has a faster onset of action than human insulin premix 70/30 and should be dosed within 15 minutes before meal initiation for patients with type 1 diabetes. For patients with type 2 diabetes, dosing should occur within 15 minutes before or after meal initiation. Injection sites should be rotated within the same region to reduce the risk of lipodystrophy. As with all insulins, the duration of action may vary according to the dose, injection site, blood flow, temperature, and level of physical activity.

NovoLog Mix 70/30 should not be administered intravenously or used in insulin infusion pumps. Dose regimens of NovoLog Mix 70/30 will vary among patients and should be determined by the health care professional familiar with the patient’s recommended glucose treatment goals, metabolic needs, eating habits, and other lifestyle variables.


Resuspension
NovoLog Mix 70/30 is a suspension that must be visually inspected and resuspended immediately before use. The NovoLog Mix 70/30 vial should be rolled gently in your hands in a horizontal position 10 times to mix it. The rolling procedure must be repeated until the suspension appears uniformly white and cloudy. Inject immediately. Resuspension is easier when the insulin has reached room temperature.

The NovoLog Mix 70/30 FlexPen should be rolled 10 times gently between your hands in a horizontal position. Thereafter, turn the NovoLog Mix 70/30 FlexPen upside down so that the glass ball moves from one end of the reservoir to the other. Do this at least 10 times. The rolling and turning procedure must be repeated until the suspension appears uniformly white and cloudy. Inject immediately. Before each subsequent injection, turn the disposable NovoLog Mix 70/30 FlexPen upside down so that the glass ball moves from one end of the reservoir to the other at least 10 times and until the suspension appears uniformly white and cloudy. Inject immediately.


WARNINGS AND PRECAUTIONS

Administration
The short and long-acting components of insulin mixes, including NovoLog Mix 70/30, cannot be titrated independently. Because NovoLog Mix 70/30 has peak pharmacodynamic activity between 1-4 hours after injection, it should be administered within 15 minutes of meal initiation. The dose of insulin required to provide adequate glycemic control for one of the meals may result in hyper- or hypoglycemia for the other meal. The pharmacodynamic profile may also be inadequate for patients who require more frequent meals.

NovoLog Mix 70/30 should not be mixed with any other insulin product.

NovoLog Mix 70/30 should not be used intravenously.

NovoLog Mix 70/30 should not be used in insulin infusion pumps.

Glucose monitoring is recommended for all patients with diabetes. Any change of insulin dose should be made cautiously and only under medical supervision. Changing from one insulin product to another or changing the insulin strength may result in the need for a change in dosage. Changes may also be necessary during illness, emotional stress, and other physiologic stress in addition to changes in meals and exercise.

The pharmacokinetic and pharmacodynamic profiles of all insulins may be altered by the site used for injection and the degree of vascularization of the site. Smoking, temperature, and exercise contribute to variations in blood flow and insulin absorption. These and other factors contribute to inter- and intra-patient variability.

Needles and NovoLog Mix 70/30 FlexPen must not be shared.


Hypoglycemia
Hypoglycemia is the most common adverse effect of insulin therapy, including NovoLog Mix 70/30. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death. Severe hypoglycemia requiring the assistance of another person and/or parenteral glucose infusion or glucagon administration has been observed in clinical trials with insulin, including trials with NovoLog Mix 70/30.

The timing of hypoglycemia may reflect the time-action profile of the insulin formulation. Other factors, such as changes in dietary intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications may also alter the risk of hypoglycemia [see Drug Interactions]. As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g. patients who are fasting or have erratic food intake). The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating machinery.

Rapid changes in serum glucose levels 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 [see Drug Interactions (7)].

Hypokalemia
All insulin products, including NovoLog Mix 70/30, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia that, if left untreated, may cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia (e.g. patients using potassium-lowering medications or patients taking medications sensitive to potassium concentrations).

Renal Impairment
Clinical or pharmacology studies with NovoLog Mix 70/30 in diabetic patients with various degrees of renal impairment have not been conducted. As with other insulins, the requirements for NovoLog Mix 70/30 may be reduced in patients with renal impairment [see Clinical Pharmacology (12.3)].

Hepatic Impairment
Clinical or pharmacology studies with NovoLog Mix 70/30 in diabetic patients with various degrees of hepatic impairment have not been conducted. As with other insulins, the requirements for NovoLog Mix 70/30 may be reduced in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

Hypersensitivity and Allergic Reactions
Local Reactions- As with other insulin therapy, patients may experience reactions such as erythema, edema or pruritus at the site of NovoLog Mix 70/30 injection. These reactions usually resolve in a few days to a few weeks, but in some occasions, may require discontinuation of NovoLog Mix 70/30. In some instances, these reactions may be related to the insulin molecule, other components in the insulin preparation including protamine and cresol, components in skin cleansing agents, or injection techniques. Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient.

Systemic Reactions- 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.

Antibody Production
Specific anti-insulin antibodies as well as cross-reacting anti-insulin antibodies were monitored in a 3-month, open-label comparator trial as well as in a long-term extension trial. Changes in cross-reactive antibodies were more common after NovoLog Mix 70/30 than with Novolin 70/30 but these changes did not correlate with change in HbA1c or increase in insulin dose. The clinical significance of these antibodies has not been established. Antibodies did not increase further after long-term exposure (>6 months) to NovoLog Mix 70/30.


ADVERSE REACTIONS
Clinical Trial Experience

Clinical trials are conducted under widely varying designs, therefore, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.

Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including NovoLog Mix 70/30. NovoLog Mix 70/30 should not be used during episodes of hypoglycemia.

Insulin initiation and glucose control intensification
Intensification or rapid improvement in glucose control has been associated with transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.

Lipodystrophy
Long-term use of insulin, including NovoLog Mix 70/30, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection sites within the same region to reduce the risk of lipodystrophy.

Weight gain
Weight gain can occur with some insulin therapies, including NovoLog Mix 70/30, and has been attributed to the anabolic effects of insulin and the decrease in glycosuria.

Peripheral Edema
Insulin may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

CLINICAL PHARMACOLOGY

Mechanism of Action
The primary activity of NovoLog Mix 70/30 is the regulation of glucose metabolism. Insulins, including NovoLog Mix 70/30, bind to the insulin receptors on muscle, liver and fat cells and lower blood glucose by facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose from the liver.

Pharmacodynamics
NovoLog Mix 70/30 has an earlier onset of action than human premix 70/30 in studies of normal volunteers and patients with diabetes. The onset of action is between 10-20 minutes for NovoLog Mix 70/30 compared to 30 minutes for Novolin 70/30. The mean ± SD time to peak activity for NovoLog Mix 70/30 is 2.4 hr ± 0.8hr compared to 4.2 hr ± 0.4 hr for Novolin 70/30. The duration of action may be as long as 24 hours

Pharmacokinetics
The single substitution of the amino acid proline with aspartic acid at position B28 in insulin aspart (NovoLog) reduces the molecule’s tendency to form hexamers as observed with regular human insulin. The rapid absorption characteristics of NovoLog are maintained by NovoLog Mix 70/30. The insulin aspart in the soluble component of NovoLog Mix 70/30 is absorbed more rapidly from the subcutaneous layer than regular human insulin. The remaining 70% is in crystalline form as insulin aspart protamine which has a prolonged absorption profile after subcutaneous injection.

Bioavailability and Absorption- The relative bioavailability of NovoLog Mix 70/30 compared to NovoLog and Novolin 70/30 indicates that the insulins are absorbed to similar extent. In euglycemic clamp studies in healthy volunteers (n=23) after dosing with NovoLog Mix 70/30 (0.2 U/kg), a mean maximum serum concentration (Cmax) of 23.4 ± 5.3 mU/L was reached after 60 minutes. The mean half-life (t1/2) of NovoLog Mix 70/30 was about 8 to 9 hours. Serum insulin levels returned to baseline 15 to 18 hours after a subcutaneous dose of NovoLog Mix 70/30. Similar data were seen in a separate euglycemic clamp study in healthy volunteers (n=24) after dosing with NovoLog Mix 70/30 (0.3 U/kg). A Cmax of 61.3 ± 20.1 mU/L was reached after 85 minutes. Serum insulin levels returned to baseline 12 hours after a subcutaneous dose.

The Cmax and the area under the insulin concentration-time curve (AUC) after administration of NovoLog Mix 70/30 was approximately 20% greater than those after administration of Novolin 70/30

Distribution and Elimination- NovoLog has a low binding to plasma proteins, 0 to 9%, similar to regular human insulin. After subcutaneous administration in normal male volunteers (n=24), NovoLog was more rapidly eliminated than regular human insulin with an average apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.

The effect of sex, age, obesity, ethnic origin, renal and hepatic impairment, pregnancy, or smoking, on the pharmacodynamics and pharmacokinetics of NovoLog Mix 70/30 has not been studied.


HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
NovoLog Mix 70/30 is available in the following package sizes: each presentation contains 100 Units of insulin aspart per mL (U-100).

10 mL vials  - NDC 0169-3685-12
3 mL NovoLog Mix 70/30 FlexPen  -  NDC 0169-3696-19

NovoLog Mix 70/30 vials and NovoLog Mix 70/30 FlexPen are latex free.


Recommended Storage
Unused NovoLog Mix 70/30 should be stored in a refrigerator between 2°C and 8°C (36°F to 46°F). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze NovoLog Mix 70/30 or use NovoLog Mix 70/30 if it has been frozen.

Vials: After initial use, a vial may be kept at temperatures below 30°C (86°F) for up to 28 days, but should not be exposed to excessive heat or sunlight. Open vials may be refrigerated.

Unpunctured vials can be used until the expiration date printed on the label if they are stored in a refrigerator. Keep unused vials in the carton so they will stay clean and protected from light.

NovoLog Mix 70/30 FlexPen: Once a NovoLog Mix 70/30 FlexPen is punctured, it should be kept at temperatures below 30°C (86°F) for up to 14 days, but should not be exposed to excessive heat or sunlight. A NovoLog Mix 70/30 FlexPen in use must NOT be stored in the refrigerator. Keep the disposable NovoLog Mix 70/30 FlexPen away from direct heat and sunlight. An unpunctured NovoLog Mix 70/30 FlexPen can be used until the expiration date printed on the label if they are stored in a refrigerator. Keep any unused NovoLog Mix 70/30 FlexPen in the carton so it will stay clean and protected from light.

These storage conditions are summarized in the following table

Not in-use (unopened)
 Room Temperature (below 30°C[86°F])
Not in-use (unopened)
Refrigerated
(2°C - 8°C [36°F- 46°F])
In-use (opened)
Room Temperature
(below 30°C[86°F])
10 mL vial 28 days Until expiration date 28 days (refrigerated/room temperature)
3mL NovoLog Mix 70/30 FlexPen 14 days Until expiration date 14 days (Do not refrigerate)




Humalog® Mix 75/25    top of page icon

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Onset
10 - 30 min
Peak1.0 - 6.5 hours
(median: 2.6 hrs)
Duration:
14 - 24 hours
Solution
Cloudy
Comments Humalog® Mix 75/25 has a duration of activity similar to that of Humulin 70/30.  Humalog® Mix75/25™ [75% insulin lispro protamine suspension and 25% insulin lispro injection] 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. Administer immediately before a meal (within 15 minutes).
Mixing
Humalog® Mix75/25™ should not be mixed with any other insulin product.

INDICATIONS AND USAGE
Humalog Mix75/25, a mixture of 75% insulin lispro protamine suspension and 25% insulin lispro injection, (rDNA origin), is indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia. Humalog Mix75/25 has a more rapid onset of glucose–lowering activity compared with Humulin 70/30 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.

DOSAGE AND ADMINISTRATION 


CLINICAL PHARMACOLOGY
Antidiabetic Activity
The primary activity of insulin, including Humalog Mix75/25, 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 Mix75/25, 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. Humalog Mix75/25 has a similar glucose–lowering effect as compared with Humulin® 70/30 on a unit for unit basis.


Pharmacokinetics
Absorption
Studies in nondiabetic subjects and patients with type 1 (insulin–dependent) diabetes demonstrated that Humalog, the rapid–acting component of Humalog Mix75/25, is absorbed faster than Regular human insulin (U–100). 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.

Humalog Mix75/25 has two phases of absorption. The early phase represents insulin lispro and its distinct characteristics of rapid onset. The late phase represents the prolonged action of insulin lispro protamine suspension. In 30 healthy nondiabetic subjects given subcutaneous doses (0.3 U/kg) of Humalog Mix75/25, peak serum concentrations were observed 30 to 240 minutes (median, 60 minutes) after dosing (see Figure 1). Identical results were found in patients with type 1 diabetes. The rapid absorption characteristics of Humalog are maintained with Humalog Mix75/25.

Humalog Mix75/25 has a more rapid absorption than Humulin 70/30, which has been confirmed in patients with type 1 diabetes.

Distribution
Radiolabeled distribution studies of Humalog Mix75/25 have not been conducted. However, 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 of Humalog Mix75/25 have not been conducted. Studies in animals indicate that the metabolism of Humalog, the rapid–acting component of Humalog Mix75/25, is identical to that of Regular human insulin.

Elimination
Humalog Mix75/25 has two absorption phases, a rapid and a prolonged phase, representative of the insulin lispro and insulin lispro protamine suspension components of the mixture. As with other intermediate-acting insulins, a meaningful terminal phase half–life cannot be calculated after administration of Humalog Mix75/25 because of the prolonged insulin lispro protamine suspension absorption.

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 Mix75/25 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 Mix75/25), 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.

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. 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 Mix75/25.

Humalog Mix75/25 has a duration of activity similar to that of Humulin 70/30.


Special Populations
Age and Gender
Information on the effect of age on the pharmacokinetics of Humalog Mix75/25 is unavailable. Pharmacokinetic and pharmacodynamic comparisons between men and women administered Humalog Mix75/25 showed no gender differences. In large Humalog clinical trials, sub-group analysis based on age and gender demonstrated that differences between Humalog and Regular human insulin in postprandial glucose parameters are maintained across sub-groups.

Smoking
The effect of smoking on the pharmacokinetics and pharmacodynamics of Humalog Mix75/25 has not been studied.

Pregnancy
The effect of pregnancy on the pharmacokinetics and pharmacodynamics of Humalog Mix75/25 has not been studied.

Obesity
The effect of obesity and/or subcutaneous fat thickness on the pharmacokinetics and pharmacodynamics of Humalog Mix75/25 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
The effect of renal impairment on the pharmacokinetics and pharmacodynamics of Humalog Mix75/25 has not been studied. 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 Mix75/25, 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. The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of Humalog Mix75/25 has not been studied. However, 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 Mix75/25, may be necessary in patients with hepatic dysfunction.

CONTRAINDICATIONS

Humalog Mix75/25 is contraindicated during episodes of hypoglycemia and in patients sensitive to insulin lispro or any of the excipients contained in the formulation.


WARNINGS
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 Mix75/25 should be given within 15 minutes before a meal.

Hypoglycemia is the most common adverse effect associated with the use of insulins, including Humalog Mix75/25. 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.


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 Mix75/25 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 Mix75/25 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 Mix75/25. 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 — As with other insulins, the requirements for Humalog Mix75/25 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 Mix75/25, 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. Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient.

Antibody Production — In clinical trials, antibodies that cross-react with human insulin and insulin lispro were observed in both human insulin mixtures and insulin lispro mixtures treatment groups.


Pregnancy
Teratogenic Effects — Pregnancy Category B
Reproduction studies with insulin lispro have been performed in pregnant rats and rabbits at parenteral doses up to 4 and 0.3 times, respectively, the average human dose (40 units/day) based on body surface area. The results have revealed no evidence of impaired fertility or harm to the fetus due to insulin lispro. There are, however, no adequate and well–controlled studies with Humalog, Humalog Mix75/25, or Humalog Mix50/50 in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

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 Mix75/25 is administered to a nursing woman. Patients with diabetes who are lactating may require adjustments in Humalog Mix75/25 dose, meal plan, or both.

Pediatric Use
Safety and effectiveness of Humalog Mix75/25 in patients less than 18 years of age have not been established.

Geriatric Use
Clinical studies of Humalog Mix75/25 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.

DOSAGE AND ADMINISTRATION
Table 1* Summary of Pharmacodynamic Properties of Insulin Products (Pooled Cross-Study Comparison)

*The information supplied in Table 1 indicates when peak insulin activity can be expected and the percent of the total insulin activity occurring during the first 4 hours. The information was derived from 3 separate glucose clamp studies in nondiabetic subjects. Values represent means, with ranges provided in parentheses.
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
(0.8 – 4.3)
70%
(49 – 89%)
Humulin R 0.32
(0.26 – 0.37)
4.4
(4.0 – 5.5)
54%
(38 – 65%)
Humalog Mix75/25 0.3 2.6
(1.0 – 6.5)
35%
(21 – 56%)
Humulin 70/30 0.3 4.4
(1.5 – 16)
32%
(14 – 60%)
Humalog Mix50/50 0.3 2.3
(0.8 – 4.8)
45%
(27 – 69%)
Humulin 50/50 0.3 3.3
(2.0 – 5.5)
44%
(21 – 60%)
NPH 0.32
(0.27 – 0.40)
5.5
(3.5 – 9.5)
14%
(3.0 – 48%)
NPL component 0.3 5.8
(1.3 – 18.3)
22%
(6.3 – 40%)


Humalog Mix75/25 is intended only for subcutaneous administration. Humalog Mix75/25 should not be administered intravenously. Dosage regimens of Humalog Mix75/25 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. Humalog Mix75/25 has a similar glucose–lowering effect as compared with Humulin 70/30 on a unit for unit basis. The quicker glucose–lowering effect of Humalog is related to the more rapid absorption rate of insulin lispro from subcutaneous tissue.

Humalog Mix75/25 starts lowering blood glucose more quickly than Regular human insulin, allowing for convenient dosing immediately before a meal (within 15 minutes). In contrast, mixtures containing Regular human insulin should be given 30 to 60 minutes before a meal.

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 Mix75/25 may vary considerably in different individuals or within the same individual. Patients must be educated to use proper injection techniques.

Humalog Mix75/25 should be inspected visually before use. Humalog Mix75/25 should be used only if it appears uniformly cloudy after mixing. Humalog Mix75/25 should not be used after its expiration date.


HOW SUPPLIED
Humalog Mix75/25 [75% insulin lispro protamine suspension and 25% insulin lispro injection, (rDNA origin)] is available in the following package sizes: each presentation containing 100 units insulin lispro per mL (U-100).
 10 mL vials NDC 0002–7511–01 (VL-7511)
 5 x 3 mL prefilled insulin delivery devices (Pen) NDC 0002–8794–59 (HP-8794)
 5 x 3 mL prefilled insulin delivery devices (KwikPen™) NDC 0002–8797–59 (HP-8797)


Storage — Humalog Mix75/25 should be stored in a refrigerator [2° to 8°C (36° to 46°F)], but not in the freezer. Do not use Humalog Mix75/25 if it has been frozen. Unrefrigerated [below 30°C (86°F)] vials must be used within 28 days or be discarded, even if they still contain Humalog Mix75/25. Unrefrigerated [below 30°C (86°F)] Pens, and KwikPens must be used within 10 days or be discarded, even if they still contain Humalog Mix75/25. 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 28 days Until expiration date 28 days, refrigerated/room temperature.
 3 mL Pen and KwikPen (prefilled) 10 days Until expiration date 10 days. Do not refrigerate.



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