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Novolog Mix 70-30

"Nov. 15, 2012 -- The number of people diagnosed with diabetes in the U.S. jumped by 50% or more in 42 states and by more than 100% in 18 of those states in just under two decades, according to the latest snapshot from the CDC.

NovoLog Mix 70/30

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

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 (insulin aspart protamine and insulin aspart (rdna origin)) has peak pharmacodynamic activity between 1-4 hours after injection, it should be administered within 15 minutes of meal initiation [see CLINICAL PHARMACOLOGY]. 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 (insulin aspart protamine and insulin aspart (rdna origin)) should not be mixed with any other insulin product.

NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) should not be used intravenously.

NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) 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.

NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) FlexPen is for use by one person only.

Hypoglycemia

Hypoglycemia is the most common adverse effect of insulin therapy, including NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) . 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 (insulin aspart protamine and insulin aspart (rdna origin)) .

The timing of hypoglycemia may reflect the time-action profile of the insulin formulation [see CLINICAL PHARMACOLOGY]. 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].

Hypokalemia

All insulin products, including NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) , 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 (insulin aspart protamine and insulin aspart (rdna origin)) 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]

Hepatic Impairment

Clinical or pharmacology studies with NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) 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]

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 (insulin aspart protamine and insulin aspart (rdna origin)) 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 (insulin aspart protamine and insulin aspart (rdna origin)) . 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 (insulin aspart protamine and insulin aspart (rdna origin)) 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.

Patient Counseling Information

[see FDA-Approved Patient Labeling]

Physician Instructions

Maintenance of normal or near-normal glucose control is a treatment goal in diabetes mellitus and has been associated with a reduction in diabetic complications. Patients should be informed about potential risks and advantages of NovoLog Mix 70/30 therapy including the possible adverse reactions. Patients should also be offered continued education and advice on insulin therapies, injection technique, life-style management, regular glucose monitoring, periodic glycosylated hemoglobin testing, recognition and management of hypo- and hyperglycemia, adherence to meal planning, complications of insulin therapy, timing of dose, instruction for use of injection devices, and proper storage of insulin. See PATIENT INFORMATION supplied with the product. Patients should be informed that frequent, patient-performed blood glucose measurements are needed to achieve optimal glycemic control and avoid both hyper- and hypoglycemia, and diabetic ketoacidosis.

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. Patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use caution when driving or operating machinery.

Accidental substitutions between NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) and other insulin products have been reported. Patients should be instructed to always carefully check that they are administering the appropriate insulin to avoid medication errors between NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) and any other insulin. The prescription for NovoLog Mix 70/30 should be written clearly in order to avoid confusion with other insulin products, for example, NovoLog or Novolin 70/30. In addition, the written prescription should clearly indicate the presentation, for example FlexPen or vial.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) . In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with NovoLog, the rapid-acting component of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) , at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area, respectively). At a dose of 200 U/kg/day, NovoLog increased the incidence of mammary gland tumors in females when compared to untreated controls. The incidence of mammary tumors found with NovoLog was not significantly different from that found with regular human insulin. The relevance of these findings to humans is not known.

NovoLog was not genotoxic in the following tests: Ames test, mouse lymphoma cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes.

In fertility studies in male and female rats, NovoLog at subcutaneous doses up to 200 U/kg/day (approximately 32 times the human subcutaneous dose, based on U/body surface area) had no direct adverse effects on male and female fertility, or on general reproductive performance of animals.

Use In Specific Populations

Pregnancy

Pregnancy Category B

All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is essential in such patients.

An open-label, randomized study compared the safety and efficacy of NovoLog (the rapid-acting component of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) ) versus human insulin in the treatment of pregnant women with Type 1 diabetes (322 exposed pregnancies (NovoLog: 157, human insulin: 165)). Two-thirds of the enrolled patients were already pregnant when they entered the study. Since only one-third of the patients enrolled before conception, the study was not large enough to evaluate the risk of congenital malformations. Mean HbA1c of ~ 6% was observed in both groups during pregnancy, and there was no significant difference in the incidence of maternal hypoglycemia.

Animal reproduction studies have not been conducted with NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) . However, subcutaneous reproduction and teratology studies have been performed with NovoLog (the rapid-acting component of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) ) and regular human insulin in rats and rabbits. In these studies, NovoLog was given to female rats before mating, during mating, and throughout pregnancy, and to rabbits during organogenesis. The effects of NovoLog did not differ from those observed with subcutaneous regular human insulin. NovoLog, like human insulin, caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32-times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area), and in rabbits at a dose of 10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area). The effects are probably secondary to maternal hypoglycemia at high doses. No significant effects were observed in rats at a dose of 50 U/kg/day and rabbits at a dose of 3 U/kg/day. These doses are approximately 8 times the human subcutaneous dose of 1.0 U/kg/day for rats and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits based on U/body surface area.

Female patients should be advised to discuss with their physician if they intend to, or if they become pregnant. There are no adequate and well-controlled studies of the use of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) in pregnant women.

Nursing Mothers

It is unknown whether insulin aspart is excreted in human milk as occurs with human insulin. There are no adequate and well-controlled studies of the use of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) or NovoLog in lactating women. Women with diabetes who are lactating may require adjustments of their insulin doses.

Pediatric Use

Safety and effectiveness of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) have not been established in pediatric patients.

Geriatric Use

Clinical studies of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) 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.

Last reviewed on RxList: 6/9/2010
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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