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NOVOLIN 70/30 Human Insulin Injection, Suspension
(70% NPH, Human Insulin Isophane Suspension and
30% Regular, Human Insulin Injection
(recombinant DNA origin) 100 units/mL) Injection

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING


1. DESCRIPTION

Novolin 70/30 is a man-made insulin (recombinant DNA origin) which is a mixture of 70% NPH, Human Insulin Isophane Suspension and 30% Regular, Human Insulin Injection that is structurally identical to the insulin produced by the human pancreas that is used to control high blood sugar in patients with diabetes mellitus.

2. INDICATIONS AND USAGE

Novolin 70/30 is indicated for the treatment of patients with diabetes mellitus for the control of hyperglycemia.

3. DOSAGE AND ADMINISTRATION

General

Dose regimens of Novolin 70/30 will vary among patients and should be determined by the health care professional familiar with the patient's metabolic needs, eating habits, and other lifestyle variables. As with all insulins, the duration of action may vary according to the dose, injection site, blood flow, temperature, and level of physical activity and conditioning.

Dosage must be individualized; fasting or preprandial blood glucose concentrations of 80—120 mg/dl or an HbA1C of < 7 are desired in adults and adolescents. Because children < 5 years of age may not be able to identify symptoms of hypoglycemia, several pediatric textbooks recommend a fasting or preprandial blood glucose concentration of 100—200 mg/dl with an HbA1C of 7.5—9. Less stringent treatment goals may also be appropriate for patients with limited life expectancies, in older adults, and in individuals with comorbid conditions. Severe or frequent hypoglycemia is an indication for the modification of treatment regimens, including setting higher glycemic goals.

Insulin dosage requirements are highly variable and can range from 0.1—2.5 units/kg/day. Most patients generally require between 0.5—1.2 units/kg/day. Initial therapy can be less aggressive in Type 2 diabetics than for Type 1 diabetes.

- For Type 1 DM, the average initial dose is 0.5—0.6 units/kg/day. Most patients will require at least 3 injections of insulin daily to achieve glycemic control.

- For Type 2 DM, the average initial dose is 0.2—0.6 units/kg/day. When used in combination with oral hypoglycemic agents, many patients with Type 2 DM can be initially controlled on a single injection of a longer-acting insulin at a dosage of 10 units or 0.2 units/kg per day; however, most patients with Type 2 DM will eventually require multiple injections and total daily doses of 1 unit/kg/day or higher. In contrast to patients with Type 1 DM, many patients with advanced Type 2 DM can be maintained on 2 injections of quick and longer-acting insulin mixtures daily.

• 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, body mass index, temperature, level of physical activity, etc.

For the treatment of type 1 diabetes mellitus or for type 2 diabetes mellitus inadequately managed by diet, exercise, and oral hypoglycemics:

NOTE: A consensus algorithm issued by the ADA and the European Association for the Study of Diabetes lists basal or intermediate-acting insulin as a second line or third line agent in patients with type 2 diabetes not controlled on oral drugs; metformin is the initial recommended therapy in all type 2 diabetics without contraindications. Once insulin is added, therapy can be intensified (e.g., addition of prandial insulin) to achieve optimal glycemic control. In patients that are receiving a sulfonylurea, the sulfonylurea should be discontinued when insulin therapy is initiated.

Subcutaneous dosage:

Adults and children: Regular insulin; isophane insulin (NPH) mixture is equipotent to other insulin mixtures. A common regimen is to give two injections per day. Initially, about 2/3 of the daily insulin dose is given before breakfast and about 1/3 is given before the evening meal. The dosage can be adjusted as necessary based on the patient's blood glucose concentrations. The injection should be administered within 30—60 minutes prior to the start of the meal.

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 occur in insulin sensitivity as renal function declines, resulting in increased responses to a given dosage. Individualize dosage based on blood glucose and other clinical parameters.

General Administration

• Regular insulin; isophane insulin (NPH) mixture is administered by subcutaneous injection only. Do not administer by intravenous or intramuscular injection.

• Visually inspect parenteral products for discoloration prior to administration whenever solution and container permit. Do not use injections which are unusually discolored. Regular insulin; isophane insulin (NPH) mixture should only be used if it is uniformly cloudy after mixing.

• Insulin pens and cartridges should never be shared among patients. Sharing may result in transmission of hepatitis viruses, HIV, or other blood-borne pathogens.

Subcutaneous (SC) Intermittent Injection Administration

• ONLY 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.

• Regular insulin; isophane insulin (NPH) mixture is preferably administered 30—60 minutes before a meal.

• Ensure that regular insulin; isophane insulin (NPH) mixture appears uniformly white and cloudy prior to injection.

- If using a vial, rotate the vial between the palms to mix before withdrawing a dose; do not shake.

- If using a pen or other injector device, rotate the device in the palms of your hand; then, turn the device upside down and back at least 10 times to mix the insulin.

- If using the Novolin 70/30 InnoLet®, tip the device up-side down and then right-side up, so that the glass ball is moved from one end of the insulin reservoir to the other, at least 10 times.

• If using a pen or other injector device, the device should be primed prior to each injection to ensure accurate dosing.

• SC injections are usually made into the anterior and lateral aspects of the thigh, the upper arms, buttocks, or the abdomen.

• Double-check dosage in syringe prior to administration.

• Lightly pinch a fold of skin; insert the needle; release the skin; inject at a 90 degree angle. Children or thin individuals can use a short needle and a 45 degree angle to avoid intramuscular injection. Aspiration is not necessary. Inject over 2—4 seconds. The needle should be remain in the skin for 5 seconds after injection to ensure complete delivery of the insulin dose.

• Rotate 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.

• Regular insulin; isophane insulin (NPH) mixture should not be diluted or mixed with any other insulins.

4. CONTRAINDICATIONS

Novolin 70/30 is contraindicated during episodes of hypoglycemia and in patients hypersensitive to Novolin 70/30 or one of its excipients.

5. MECHANISM OF ACTION

Insulin lowers glucose concentrations by facilitating the uptake of glucose in muscle and adipose tissue and by inhibiting hepatic glucose production (glycogenolysis and gluconeogenesis). Insulin also regulates fat metabolism by enhancing the storage of fat (lipogenesis) and inhibiting the mobilization of fat for energy in adipose tissues (lipolysis and free fatty acid oxidation). Finally, insulin is involved in the regulation of protein metabolism by increasing protein synthesis and inhibiting proteolysis in muscle tissue.

Diabetes mellitus type 1 is caused by insulin deficiency while diabetes mellitus type 2 is caused by a combination of insulin deficiency and resistance. Biosynthetic insulin is used as replacement therapy in patients with diabetes mellitus 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.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Teratogenic Effects – Pregnancy Category B

Fetal abnormalities in animal studies of insulin have not been reported when insulin is used at doses similar to those that would be used in humans; however, high doses of insulin inducing maternal hypoglycemia have been associated with fetal toxicity such as pre- and post-implantation losses and visceral/skeletal abnormalities. Novolin 70/30 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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. Most experts recommend human insulin as the therapy of choice to maintain blood glucose as close to normal as possible during pregnancy in patients with Type 1 or 2 diabetes mellitus, and, if diet therapy alone is not successful, for those patients with gestational diabetes. Optimizing glycemic control before conception and during pregnancy appears to improve fetal outcome; this should include the avoidance of episodes of hypoglycemia as the toxic effects of maternal hypoglycemia on the fetus have been well-documented. During the perinatal period, careful monitoring of neonates born to mothers with diabetes is recommended. Post-partum, maternal insulin requirements may need adjustment.

6.2 Nursing Mothers

The extent of excretion of insulin into breast milk is unknown. Insulin is degraded in the gastrointestinal tract; therefore, any insulin secreted into breast milk would not be absorbed by a breast-feeding infant. The American Diabetes Association encourages breast-feeding in women with pre-existing diabetes mellitus or gestational diabetes; accordingly, women on insulin therapy should be encouraged to breast-feed if no other contraindications exist. Breast-feeding, however, may decrease insulin requirements, despite the need for increased caloric intake. Careful observation of increased maternal caloric needs and maternal blood glucose levels are needed.

6.3 Pediatric Patients

Safety and effectiveness of Novolin 70/30 in children have not been established.

6.4 Geriatric Patients

Clinical studies of Novolin 70/30 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 be cautious, usually starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this population.

7. WARNINGS AND PRECAUTIONS

WARNINGS

Novolin 70/30 should not be administered intravenously.

Novolin 70/30 is not to be used in insulin infusion pumps.

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

Hypoglycemia is the most common adverse effect of insulin therapy, including Novolin 70/30. 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 dose should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type (e.g., regular, NPH, analog), species (animal, human), or method of manufacture (rDNA versus animal-source insulin) 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 Novolin 70/30 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).

Fixed ratio insulins are typically dosed on a twice daily basis, i.e., before breakfast and supper, with each dose intended to cover two meals or a meal and snack (see DOSAGE AND ADMINISTRATION). 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 (e.g. pregnant women) who require more frequent meals.

Adjustments in insulin dose or insulin type may be needed 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.

Lipodystrophy and hypersensitivity are among other potential clinical adverse effects associated with the use of all insulins.

Renal Impairment– Clinical or pharmacology studies with Novolin 70/30 in diabetic patients with various degrees of renal impairment have not been conducted. As with other insulins, the requirements for Novolin 70/30 may be reduced in patients with renal impairment.

Hepatic Impairment– Clinical or pharmacology studies with Novolin 70/30 in diabetic patients with various degrees of hepatic impairment have not been conducted. As with other insulins, the requirements for Novolin 70/30 may be reduced in patients with hepatic impairment.

Allergy– Local Reactions– Erythema, swelling, and pruritus at the injection site have been observed with Novolin 70/30 as with other insulin therapy. 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.

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. Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient.

Antibody production– Specific anti-insulin antibodies as well as cross-reacting anti-insulin antibodies were monitored in the 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.

8. ADVERSE REACTIONS

Adverse events commonly associated with human insulin therapy include the following:

Body as whole: Allergic reactions (see PRECAUTIONS, Allergy).

Hypoglycemia: Insulin facilitates the intracellular uptake of potassium, therefore, hypokalemia is possible.

Weight gain: Insulin therapy has been associated with weight gain. In the diabetes control and complications trial (DCCT), intensive insulin therapy in type 1 diabetes patients was associated with a weight gain of 4.6 kg more at five years when compared to those patients in the conventional therapy group.

Injection site reactions: During insulin therapy, an injection site reaction 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). Lipodystrophy reactions can be avoided by rotating the sites of injection so that a site is not used more than once every 1—2 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.

Peripheral edema may occur in patients taking insulin therapy. Sodium retention and edema are especially possible if previously poor metabolic control is improved by intensified insulin therapy.

Other: Small elevations in alkaline phosphatase were observed in patients treated in NovoLog® controlled clinical trials. There have been no clinical consequences of these laboratory findings.

9. OVERDOSAGE

Excess insulin may cause hypoglycemia and hypokalemia, particularly after IV administration. 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. Hypokalemia must be corrected appropriately.

10. DRUG INTERACTIONS

A number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring.

• The following are examples of substances that may reduce insulin requirement: oral hypoglycemic agents (OHA), octreotide, monoamine oxidase inhibitors (MAOI), non-selective beta-blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates, alcohol, sulphonamide antibiotics, anabolic steroids, quinine, quinidine and alpha-adrenergic blocking agents.

• The following are examples of substances that may increase insulin requirement: oral contraceptives, thiazides, glucocorticoids, thryroid hormones and sympathomimetics, growth hormone, diazoxide, asparaginase and nicotinic acid.

• Beta-blocking agents may mask the symptoms of hypoglycemia and delay recovery from hypoglycemia.

• Alcohol may intensify and prolong the hypoglycemic effect of insulin.

11. PHARMACOKINETICS

Endogenous 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 endogenous insulin is approximately 5—6 minutes.

The onset of action of regular insulin begins approximately 30 minutes with maximal effects occurring 1—3 hours after SC injection. The apparent plasma half-life following SC administration is approximately 1.5 hours with a duration of action of 8—12 hours. Subcutaneously administered regular insulin is best given 30—60 minutes before a meal.

After subcutaneous administration, the onset of glucose lowering activity of isophane insulin (NPH) begins approximately 1—4 hours after injection with maximal activity occurring between 4 and 14 hours (mean 5.5 hours). Roughly 14% of the total activity occurs in the first 4 hours (range 3.0—48%). The duration of glucose lowering activity ranges from 10—24 hours or longer.

The onset of glucose lowering activity of regular insulin; isophane insulin (NPH) is approximately 30 minutes after subcutaneous administration with time to peak activity occurring at 3.3—4.4 hours (range 1.5—16 hours). The duration of action of regular insulin; isophane insulin (NPH) is similar to that of NPH insulin (10—24 hours).

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand names: NOVOLIN 70/30, by Novo Nordisk.

b) Generic drugs:INSULIN RECOMBINANT HUMAN; INSULIN SUSP ISOPHANE RECOMBINANT HUMAN, by Lilly.

2) How Supplied:

Novolin 70/30 is available in the following package sizes: each presentation contains 30 Units of insulin recombinant human and 70 Units of insulin susp isophane recombinant human per mL (U-100).

10 mL vials

3 mL Novolin 70/30 FlexPen® prefilled syringe

3) Storage:

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).

• If refrigeration is not possible, the unopened PenFill cartridge or InnoLet prefilled syringe may be kept at room temperature for up to 10 days, as long as it is kept at or below 86°F (30°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.

PenFill Cartridges

• Keep at room temperature below 86°F (30°C) for up to 10 days.

• Do not store a PenFill cartridge that you are using in the refrigerator.

• Keep PenFill cartridges away from direct heat or light.

• Throw away a used PenFill cartridge after 10 days, even if there is insulin left in the cartridge.

InnoLet prefilled syringe

• Keep at room temperature below 86°F (30°C) for up to 10 days.

• Do not store an InnoLet prefilled syringe that you are using in the refrigerator.

• Keep InnoLet prefilled syringes away from direct heat or light.

• Throw away a used InnoLet prefilled syringe after 10 days, even if there is insulin left in the prefilled syringe.

Class: Over-the-counter 

Rev 10/07