warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypoglycemia: Most common adverse reaction of insulin therapy and may be life-threatening. Closely monitor blood glucose. Changes in insulin or dosage should be made cautiously and only under medical supervision ( ). • 5.2 Hypokalemia: Particularly when insulin is given intravenously or in settings of poor glycemic control. Use caution in patients predisposed to hypokalemia ( ). • 5.3 Renal or hepatic impairment: As with other insulins, the dose requirements for Novolin R may be reduced ( ). • 5.5 Allergic reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, may occur ( ). • 5.6 Mixing: Do not mix Novolin R with any insulin for intravenous use. Do not mix with insulins other than NPH insulin for subcutaneous use ( ). • 5.7 Fluid retention and heart failure can occur with concomitant use of thiazolidinediones (TZDs), which are PPAR-gamma agonists, and insulin, including Novolin R ( ). • 5.9 5.1 Administration Subcutaneous injection of Novolin R should be followed by a meal. Patients should wait approximately 30 minutes after injection before starting the meal [ ]. see Dosage and Administration ( ) 2.2 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. As with all insulin preparations, the time course of Novolin R action may vary in different individuals or at different times in the same individual and is dependent on many conditions, including dosage, the site of injection, local blood supply, temperature, and physical activity. Patients who change their level of physical activity or meal plan may require adjustment of insulin dosages. Insulin requirements may be altered during illness, emotional disturbances, or other stresses. 5.2 Hypoglycemia Hypoglycemia is the most common adverse reaction of all insulin therapies, including Novolin R. Severe hypoglycemia may lead to unconsciousness, convulsions, temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person, parenteral glucose infusion, and glucagon administration has been observed in clinical trials with insulin, including trials with Novolin R. The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations [ ]. Other factors such as changes in food intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications may also alter the risk of hypoglycemia [ ]. 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, pediatric patients, and the elderly). 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 other machinery. see Clinical Pharmacology ( , ) 12.2 12.3 see Drug Interactions ( ) 7 Rapid changes in serum glucose concentrations may induce symptoms of hypoglycemia in patients with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic neuropathy, use of medications such as beta-blockers, or intensified glycemic control [ ]. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of hypoglycemia. Intravenously administered insulin has a more rapid onset of action than subcutaneously administered insulin, requiring more close monitoring for hypoglycemia. see Drug Interactions ( ) 7 5.3 Hypokalemia All insulins, including Novolin R, 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 and patients taking medications sensitive to serum potassium concentrations). Monitor glucose and potassium frequently when Novolin R is administered intravenously. 5.4 Hyperglycemia, Diabetic Ketoacidosis, and Hyperosmolar Hyperglycemic Non-Ketotic Syndrome Hyperglycemia, diabetic ketoacidosis, or hyperosmolar hyperglycemic non-ketotic syndrome may develop in patients who take less insulin than needed to control blood glucose. These conditions can be precipitated by illness, infection, dietary indiscretion, or omission or improper administration of the prescribed insulin dose. 5.5 Renal or Hepatic Impairment As with other insulins, the dose requirements for Novolin R may be reduced in patients with renal or hepatic impairment. 5.6 Hypersensitivity and Allergic Reactions - As with other insulins, patients may experience redness, swelling, or itching at the site of injection of Novolin R. These reactions usually resolve in a few days to a few weeks, but in some occasions, may require discontinuation of Novolin R. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Localized reactions and generalized myalgias have been reported with the use of meta-cresol, which is an excipient in Novolin R. Local Reactions - Severe, life-threatening, generalized allergy, including anaphylaxis may occur with any insulin, including Novolin R. Generalized allergy to insulin may manifest as a whole body rash (including pruritus), dyspnea, wheezing, hypotension tachycardia, or diaphoresis. Systemic Reactions , 5.7 Mixing of Insulins If Novolin R is mixed with NPH human insulin, Novolin R should be drawn into the syringe first and the mixture should be injected immediately after mixing. Insulin mixtures should not be administered intravenously. 5.8 Antibody Production Increases in titers of anti-insulin antibodies that react with human insulin have been observed in patients treated with Novolin R. Data from a 12-month controlled trial in patients with type 1 diabetes suggest that the increase in these antibodies is transient. The clinical significance of these antibodies is not known but does not appear to cause deterioration in glycemic control or necessitate increases in insulin dose. 5.9 Fluid retention and heart failure with concomitant use of PPAR-gamma agonists Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including NOVOLIN R, 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.