Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied NOVOLIN N (insulin isophane human) injectable suspension, 100 units/mL (U-100), is a white and cloudy suspension available as: 10 mL multiple-dose vial NDC 0169-1834-11 ReliOn ® brand NDC 0169-1834-02 3 mL single-patient-use FlexPen prefilled pen NDC 0169-3004-15 ReliOn ® brand NDC 0169-3004-25 The NOVOLIN N FlexPen dials in 1-unit increments. 16.2 Storage and Handling Dispense in the original sealed carton with the enclosed Instructions for Use. Do not expose NOVOLIN N vials and NOVOLIN N FlexPen to excessive heat or light. Do not freeze. Do not use after the expiration date. NOVOLIN N FlexPen must never be shared between patients, even if the needle is changed. Always remove and discard the needle after each injection from the NOVOLIN N FlexPen and store without a needle attached. Patients using NOVOLIN N vials must never share needles or syringes with another person. Always use a new disposable syringe or needle for each injection to prevent contamination. Table 2: Storage Conditions and Expiration Dates for NOVOLIN N Not In-use (Unopened) Refrigerated (36°F - 46°F [2°C - 8°C]) Not In-use (Unopened) Room Temperature (see temperature below) In-use (Opened) Room Temperature (see temperature below) 10 mL multiple-dose vial Until expiration date 42 days up to 77°F (25°C) 42 days up to 77°F (25°C) (Do not refrigerate) 3 mL single-patient-use FlexPen Until expiration date 28 days up to 86°F (30°C) 28 days up to 86°F (30°C) (Do not refrigerate); PRINCIPAL DISPLAY PANEL – 10 mL vial NDC 0169-1834-11 Novolin ® N NPH (insulin isophane human) injectable suspension 100 units/mL (U-100) For subcutaneous use only 10 mL multiple-dose vial Novo Nordisk ® Image of Novolin N vial carton; PRINCIPAL DISPLAY PANEL – 10 mL vial ReliOn NDC 0169-1834-02 Novolin® N NPH (insulin isophane human) injectable suspension 100 units/mL (U-100) For subcutaneous use only 10 mL multiple-dose vial ReliOn ® Image of Novolin N vial carton - ReliOn; PRINCIPAL DISPLAY PANEL – 3 mL FlexPen NDC 0169-3004-15 List 300415 Novolin ® N FlexPen ® NPH (insulin isophane human) injectable Suspension For Single Patient Use Only 100 units/mL (U-100) 5×3 mL Prefilled Pens For subcutaneous use only Recommended for use with NovoFine ® , NovoFine ® Plus or NovoTwist ® disposable needles. Store unopened pens refrigerated at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light until expiration date or first use. Do not freeze. After first use, store at room temperature (up to 86°F (30°C) and discard after 28 days. Dispense in this sealed carton. Shake carefully before using. See enclosed insert for proper technique. N novo nordisk ® Image of Novolin N FlexPen carton; PRINCIPAL DISPLAY PANEL – 3 mL FlexPen ReliOn NDC 0169-3004-25 List 300425 Novolin ® N FlexPen ® NPH (insulin isophane human) injectable suspension For Single Patient Use Only 100 units/mL (U-100) 5×3 mL Prefilled Pens For subcutaneous use only Recommended for use with NovoFine ® , NovoFine ® Plus or NovoTwist ® disposable needles. Store unopened pens refrigerated at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light until expiration date or first use. Do not freeze. After first use, store at room temperature (up to 86°F (30°C) and discard after 28 days. Dispense in this sealed carton. Shake carefully before using. See enclosed insert for proper technique. N ReliOn ® Image of Novolin N FlexPen carton - ReliOn
- 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied NOVOLIN N (insulin isophane human) injectable suspension, 100 units/mL (U-100), is a white and cloudy suspension available as: 10 mL multiple-dose vial NDC 0169-1834-11 ReliOn ® brand NDC 0169-1834-02 3 mL single-patient-use FlexPen prefilled pen NDC 0169-3004-15 ReliOn ® brand NDC 0169-3004-25 The NOVOLIN N FlexPen dials in 1-unit increments. 16.2 Storage and Handling Dispense in the original sealed carton with the enclosed Instructions for Use. Do not expose NOVOLIN N vials and NOVOLIN N FlexPen to excessive heat or light. Do not freeze. Do not use after the expiration date. NOVOLIN N FlexPen must never be shared between patients, even if the needle is changed. Always remove and discard the needle after each injection from the NOVOLIN N FlexPen and store without a needle attached. Patients using NOVOLIN N vials must never share needles or syringes with another person. Always use a new disposable syringe or needle for each injection to prevent contamination. Table 2: Storage Conditions and Expiration Dates for NOVOLIN N Not In-use (Unopened) Refrigerated (36°F - 46°F [2°C - 8°C]) Not In-use (Unopened) Room Temperature (see temperature below) In-use (Opened) Room Temperature (see temperature below) 10 mL multiple-dose vial Until expiration date 42 days up to 77°F (25°C) 42 days up to 77°F (25°C) (Do not refrigerate) 3 mL single-patient-use FlexPen Until expiration date 28 days up to 86°F (30°C) 28 days up to 86°F (30°C) (Do not refrigerate)
- PRINCIPAL DISPLAY PANEL – 10 mL vial NDC 0169-1834-11 Novolin ® N NPH (insulin isophane human) injectable suspension 100 units/mL (U-100) For subcutaneous use only 10 mL multiple-dose vial Novo Nordisk ® Image of Novolin N vial carton
- PRINCIPAL DISPLAY PANEL – 10 mL vial ReliOn NDC 0169-1834-02 Novolin® N NPH (insulin isophane human) injectable suspension 100 units/mL (U-100) For subcutaneous use only 10 mL multiple-dose vial ReliOn ® Image of Novolin N vial carton - ReliOn
- PRINCIPAL DISPLAY PANEL – 3 mL FlexPen NDC 0169-3004-15 List 300415 Novolin ® N FlexPen ® NPH (insulin isophane human) injectable Suspension For Single Patient Use Only 100 units/mL (U-100) 5×3 mL Prefilled Pens For subcutaneous use only Recommended for use with NovoFine ® , NovoFine ® Plus or NovoTwist ® disposable needles. Store unopened pens refrigerated at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light until expiration date or first use. Do not freeze. After first use, store at room temperature (up to 86°F (30°C) and discard after 28 days. Dispense in this sealed carton. Shake carefully before using. See enclosed insert for proper technique. N novo nordisk ® Image of Novolin N FlexPen carton
- PRINCIPAL DISPLAY PANEL – 3 mL FlexPen ReliOn NDC 0169-3004-25 List 300425 Novolin ® N FlexPen ® NPH (insulin isophane human) injectable suspension For Single Patient Use Only 100 units/mL (U-100) 5×3 mL Prefilled Pens For subcutaneous use only Recommended for use with NovoFine ® , NovoFine ® Plus or NovoTwist ® disposable needles. Store unopened pens refrigerated at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light until expiration date or first use. Do not freeze. After first use, store at room temperature (up to 86°F (30°C) and discard after 28 days. Dispense in this sealed carton. Shake carefully before using. See enclosed insert for proper technique. N ReliOn ® Image of Novolin N FlexPen carton - ReliOn
Overview
Insulin isophane human is produced by recombinant DNA technology, utilizing Saccharomyces cerevisiae (baker’s yeast) as the production organism. Insulin isophane human is a suspension of crystals produced from combining human insulin and protamine sulfate under appropriate conditions for crystal formation. The amino acid sequence of insulin isophane human is identical to human insulin and has the empirical formula C 257 H 383 N 65 O 77 S 6 and a molecular weight of 5808 Da. Figure 1: Structural formula of human insulin NOVOLIN N (insulin isophane human) injectable suspension is an intermediate acting human insulin. It is a sterile, white and cloudy suspension that contains insulin isophane human suspension (NPH) for subcutaneous use. Each milliliter of Novolin N contains 100 units of insulin human, dibasic sodium phosphate (1.9 mg), glycerin (16 mg), metacresol (1.5 mg), phenol (0.65 mg), protamine sulfate (approximately 0.35 mg), zinc (33.5 mcg for the vial or 33.2 mcg for the FlexPen), and Water for Injection. Hydrochloric acid 2N and sodium hydroxide 2N may be added to adjust the pH. The pH is 7.1 to 7.5. Structural Formula Novolin R
Indications & Usage
NOVOLIN N is indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus. NOVOLIN N is an intermediate-acting human insulin indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus. ( 1 )
Dosage & Administration
• See Full Prescribing Information for important administration instructions. ( 2.1 ) • Inject subcutaneously in abdominal wall, thigh, upper arm, or buttocks and rotate injection sites to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. ( 2.1 ) • Individualize and adjust dosage based on metabolic needs, blood glucose monitoring results and glycemic control goal. ( 2.2 ) • Administer NOVOLIN N once or twice daily. ( 2.2 ) • In patients with type 1 diabetes, NOVOLIN N should generally be used in regimens that include a short-acting insulin. ( 2.2 ) • NOVOLIN N can be mixed with NOVOLIN R. ( 2.4 ) 2.1 Important Administration Instructions • Always check insulin labels before administration [see Warnings and Precautions ( 5.4 )]. • NOVOLIN N is a suspension that must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature. • To resuspend vial, roll the vial gently in your hands in a horizontal position 10 times until the suspension appears uniformly white and cloudy. Inject immediately. • To resuspend FlexPen, gently move the pen up and down 20 times so the glass ball moves from one end of the cartridge to the other until the suspension appears uniformly white and cloudy. Inject immediately. • Inspect NOVOLIN N visually before use. Do not use NOVOLIN N if discoloration or particulate matter is seen. • Administer NOVOLIN N by subcutaneous injection in the abdominal wall, thigh, upper arm, or buttocks. • Rotate the injection site within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions ( 5.2 ), Adverse Reactions ( 6 )] . • During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )] . • Do not administer NOVOLIN N intravenously and do not use in an insulin infusion pump. 2.2 Dosage Information • Individualize and adjust the dosage of NOVOLIN N based on the individual's metabolic needs, blood glucose monitoring results and glycemic control goal. • Administer NOVOLIN N once or twice daily. • In patients with type 1 diabetes, NOVOLIN N should generally be used in regimens that include a short-acting insulin. • Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness [see Warnings and Precautions ( 5.2 , 5.3 ) and Use in Specific Populations ( 8.6 , 8.7 )]. • Dosage adjustment may be needed when switching from another insulin to NOVOLIN N [see Warnings and Precautions ( 5.2 )]. 2.3 Dosage Adjustment due to Drug Interactions • Dosage adjustment may be needed when NOVOLIN N is co-administered with certain drugs [see Drug Interactions ( 7 )] . 2.4 Instructions for Mixing with Other Insulins • NOVOLIN N can be mixed in the same syringe with NOVOLIN R. • When mixing, the NOVOLIN R should be drawn into the syringe first, followed by the NOVOLIN N. The mixture should be injected immediately after mixing.
Warnings & Precautions
• Never share a NOVOLIN N FlexPen or syringe between patients, even if the needle is changed. ( 5.1 ) • Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen: Make changes to a patient’s insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. ( 5.2 ) • Hypoglycemia: May be life-threatening. Increase frequency of blood glucose monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; in patients with renal or hepatic impairment; and in patients with hypoglycemia unawareness. ( 5.3 ) • Hypoglycemia Due to Medication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. ( 5.4 ) • Hypersensitivity Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue NOVOLIN N, monitor, and treat if indicated. ( 5.5 ) • Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated. ( 5.6 ) • Fluid Retention and Heart Failure with Concomitant Use of Thiazolidinediones (TZDs) : Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. ( 5.7 ) 5.1 Never Share a NOVOLIN N FlexPen or Syringe between Patients NOVOLIN N FlexPen must never be shared between patients, even if the needle is changed. Patients using NOVOLIN N vials must never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens. 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions ( 5.3 )] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions ( 6 )] . Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments of concomitant anti-diabetic products may be needed. 5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction of all insulins, including NOVOLIN N. Severe hypoglycemia can cause seizures, may lead to unconsciousness may be life threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place the patient and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). Hypoglycemia can happen suddenly and symptoms may differ in each patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes in patients with diabetic neuropathy, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions ( 7 )] , or in patients who experience recurrent hypoglycemia. Risk Factors for Hypoglycemia The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulins, the glucose lowering effect time course of NOVOLIN N may vary in different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature. Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to concomitant drugs [see Drug Interactions ( 7 )]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations ( 8.6 , 8.7 )]. Risk Mitigation Strategies for Hypoglycemia Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. 5.4 Hypoglycemia Due to Medication Errors Accidental mix-ups between NOVOLIN N and other insulin products have been reported. To avoid medication errors between NOVOLIN N and other insulins, instruct patients to always check the insulin label before each injection. 5.5 Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with NOVOLIN N. Generalized allergy to insulin may manifest as a whole body rash (including pruritus), dyspnea, wheezing, hypotension , tachycardia, or diaphoresis. If hypersensitivity reactions occur, discontinue NOVOLIN N, treat per standard of care and monitor until symptoms and signs resolve. NOVOLIN N is contraindicated in patients who have had hypersensitivity reactions to isophane insulin human or its excipients . 5.6 Hypokalemia All insulins, including NOVOLIN N, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentration). 5.7 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 when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including NOVOLIN N, 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 current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.
Contraindications
NOVOLIN N is contraindicated: • During episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] • In patients who have hypersensitivity reactions to NOVOLIN N or any of its excipients [see Warnings and Precautions ( 5.5 )] • During episodes of hypoglycemia ( 4 ) • Hypersensitivity to NOVOLIN N or any of its excipients ( 4 )
Adverse Reactions
The following adverse reactions are also discussed elsewhere in the labeling: • Hypoglycemia [see Warnings and Precautions ( 5.3 )] • Hypoglycemia Due to Medication Errors [see Warnings and Precautions ( 5.4 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.5 )] • Hypokalemia [see Warnings and Precautions ( 5.6 )] Adverse Reactions from Clinical Studies or Postmarketing Reports The following additional adverse reactions have been identified during clinical studies or from postmarketing reports with use of NOVOLIN N. Because some of these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. Adverse reactions associated with insulin initiation and glucose control intensification Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. Over the long-term, improved glycemic control decreases the risk of diabetic retinopathy and neuropathy. Hypersensitivity reactions Severe, life-threatening, generalized allergy, including anaphylaxis. Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in NOVOLIN N. Hypokalemia NOVOLIN N can cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Injection site reactions NOVOLIN N can cause local injection site reactions including redness, swelling, or itching at the site of injection. These reactions usually resolve in a few days to a few weeks, but in some occasions, may require discontinuation. Localized reactions and generalized myalgias have been reported with the use of metacresol, which is an excipient in NOVOLIN N. Lipodystrophy Administration of insulin subcutaneously, including NOVOLIN N, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) [see Dosage and Administration ( 2.1 )] in some patients. Localized Cutaneous Amyloidosis Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site. Medication Errors Medication errors in which other insulins have been accidentally substituted for NOVOLIN N have been identified during postapproval use. Peripheral edema Insulins, including NOVOLIN N, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Weight gain Weight gain can occur with insulins including NOVOLIN N, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Immunogenicity As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The incidence of antibody formation with NOVOLIN N is unknown. Adverse reactions observed with NOVOLIN N include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, weight gain and edema. ( 6 ) 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.
Drug Interactions
Table 1: Clinically Significant Drug Interactions with NOVOLIN N Drugs that May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLIN N is co-administered with these drugs. Drugs that May Decrease the Blood Glucose Lowering Effect of NOVOLIN N Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLIN N is co-administered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of NOVOLIN N Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLIN N is co-administered with these drugs. Drugs that May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine, and reserpine Intervention: Increased frequency of glucose monitoring may be required when NOVOLIN N is co-administered with these drugs. • Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may be needed. ( 7 ) • Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent. ( 5.3 , 7 )
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