Insulin Aspart Protamine and Insulin Aspart

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 [see WARNINGS AND PRECAUTIONS]. NovoLog Mix 70/30 should not be used during episodes of hypoglycemia [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
• 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 (insulin aspart protamine and insulin aspart (rdna origin)) , 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 (insulin aspart protamine and insulin aspart (rdna origin)) , 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.
• Frequencies of adverse drug reactions
  The frequencies of adverse drug reactions during a clinical trial with NovoLog Mix 70/30 in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below. The trial was a three-month, open-label trial in patients with Type 1 or Type 2 diabetes who were treated twice daily (before breakfast and before supper) with NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) .

Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 diabetes mellitus (Adverse events with frequency ≥ 5% are included.)

Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 diabetes mellitus (Adverse events with frequency ≥ 5% are included.)

Postmarketing Data

Additional adverse reactions have been identified during post-approval use of NovoLog Mix 70/30 (insulin aspart protamine and insulin aspart (rdna origin)) . Because these adverse reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency. They include medication errors in which other insulins have been accidentally substituted for NovoLog Mix 70/30 [see PATIENT INFORMATION].

Included as part of the PRECAUTIONS section.

• Aspart Insulin and Insulin Aspart Protamine
• Insulin Aspart and Insulin Aspart Protamine
• NovoLog 70/30

• NovoLOG Mix 70/30
• NovoLOG Mix 70/30 FlexPen

• Insulin, Combination

Insulin Cl may be reduced in patients with impaired renal function.

Refer to indication-specific dosing for obesity-related information (may not be available for all indications).

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Beta-Blockers: May enhance the hypoglycemic effect of Insulin. Exceptions: Levobunolol; Metipranolol. Monitor therapy

DPP-IV Inhibitors: May enhance the hypoglycemic effect of Insulin. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Edetate CALCIUM Disodium: May enhance the hypoglycemic effect of Insulin. Monitor therapy

Edetate Disodium: May enhance the hypoglycemic effect of Insulin. Monitor therapy

GLP-1 Agonists: May enhance the hypoglycemic effect of Insulin. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Exceptions: Liraglutide. Consider therapy modification

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Liraglutide: May enhance the hypoglycemic effect of Insulin. Management: If liraglutide is used for the treatment of diabetes (Victoza), consider insulin dose reductions. The combination of liraglutide and insulin should be avoided if liraglutide is used exclusively for weight loss (Saxenda). Consider therapy modification

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Metreleptin: May enhance the hypoglycemic effect of Insulin. Management: Insulin dosage adjustments (including potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of metreleptin. Monitor closely. Consider therapy modification

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pioglitazone: May enhance the adverse/toxic effect of Insulin. Specifically, the risk for hypoglycemia, fluid retention, and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone, dose reductions should be considered to reduce the risk of hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure. Consider therapy modification

Pramlintide: May enhance the hypoglycemic effect of Insulin. Management: Upon initiation of pramlintide, decrease mealtime insulin dose by 50% to reduce the risk of hypoglycemia. Monitor blood glucose frequently and individualize further insulin dose adjustments based on glycemic control. Consider therapy modification

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Rosiglitazone: Insulin may enhance the adverse/toxic effect of Rosiglitazone. Specifically, the risk of fluid retention, heart failure, and hypoglycemia may be increased with this combination. Avoid combination

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

SGLT2 Inhibitors: May enhance the hypoglycemic effect of Insulin. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Frequency not defined.

Cardiovascular: Palpitations, peripheral edema, tachycardia

Central nervous system: Confusion, fatigue, headache, hypothermia, loss of consciousness, myasthenia, paresthesia

Dermatologic: Diaphoresis, erythema, pallor, pruritus, skin rash, urticaria

Endocrine & metabolic: Hypoglycemia, hypokalemia, lipodystrophy, weight gain

Gastrointestinal: Hunger, nausea, oral paresthesia

Hypersensitivity: Anaphylaxis, hypersensitivity reaction (systemic symptoms), local insulin hypersensitivity reaction

Immunologic: Antibody development (no change in efficacy)

Local: Injection site reaction (including itching at injection site, pain at injection site, stinging at injection site, or warm sensation at injection site)

Neuromuscular & skeletal: Lipoatrophy, tremor

Ophthalmic: Blurred vision, presbyopia (transient)

Animal reproduction studies have not been conducted. Biphasic insulin aspart (insulin aspart protamine suspension 70% [intermediate acting] and insulin aspart solution 30% [rapid acting]) was found to be comparable to biphasic human insulin (Insulin NPH suspension 70% [intermediate acting] and insulin regular solution 30% [short acting]) in initial studies of women with gestational diabetes mellitus (Balaji 2010; Balaji 2012).

In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2017c; Kitzmiller 2008; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ACOG 2013; ADA 2017c; Blumer 2013; Kitzmiller 2008; Lambert 2013).

Insulin therapy is the preferred treatment of type 1 and type 2 diabetes in pregnant women, as well as GDM when pharmacologic therapy is needed (ADA 2017c). Insulin requirements tend to fall during the first trimester of pregnancy and increase in the later trimesters, peaking at 28 to 32 weeks of gestation. Following delivery, insulin requirements decrease rapidly (ACOG 2005).

Most available information for use of insulin aspart in pregnancy is from studies using the rapid action solution. Refer to Insulin Aspart monograph for additional information.