The following Structured Product Label (SPL) was submitted to the FDA by Novo Nordisk for the product Novolog Mix 70/30 (NDC 0169-2200). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1 indications and usage, 2.1 important administration information, 2.2 dosage information, 2.3 dosage adjustment due to drug interactions, 3 dosage forms and strengths, 4 contraindications, 5.1 never share novolog mix 70/30 flexpen between patients, 5.2 hyperglycemia or hypoglycemia with changes in insulin regimen, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
NOVOLOG MIX 70/30 is a mixture of insulin aspart protamine and insulin aspart indicated to improve glycemic control in patients with diabetes mellitus.
Limitations of Use:
NOVOLOG MIX 70/30 is 100 units per mL (U-100), 70% insulin aspart protamine and 30% insulin aspart, is available as a white and cloudy injectable suspension:
NOVOLOG MIX 70/30 is contraindicated
NOVOLOG MIX 70/30 FlexPen should never be shared between patients, even if the needle is changed. Patients using NOVOLOG MIX 70/30 vials must never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.
Changes in insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions (5.3)]or hyperglycemia. These changes should be made cautiously and only under close medical supervision, and the frequency of blood glucose monitoring should be increased. For patients with type 2 diabetes, dosage adjustments of concomitant anti-diabetic products may be needed.
Hypoglycemia is the most common adverse effect of all insulin therapies, including NOVOLOG MIX 70/30. 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 an individual 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 individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes in patients with diabetic nerve disease, 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 insulin preparations, the glucose lowering effect time course of NOVOLOG MIX 70/30 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 [see Clinical Pharmacology (12.2)]. 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 co-administered medication [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; increased frequency of blood glucose monitoring is recommended. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.
Accidental mix-ups between NOVOLOG MIX 70/30 and other insulin products have been reported. To avoid medication errors between NOVOLOG MIX 70/30 and other insulins, instruct patients to always check the insulin label before each injection.
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including NOVOLOG MIX 70/30. If hypersensitivity reactions occur, discontinue NOVOLOG MIX 70/30; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6)]. NOVOLOG MIX 70/30 is contraindicated in patients who have had hypersensitivity reactions to insulin aspart or one of the excipients [see Contraindications (4)].
All insulin products, including NOVOLOG MIX 70/30, can 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).
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 NOVOLOG MIX 70/30, 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.
The following adverse reactions are also discussed elsewhere:
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. The data in Table 1 reflect the exposure of 55 patients with type 1 diabetes to NOVOLOG MIX 70/30 with a mean exposure duration of three months. The mean age was 43.2 years. Sixty-four percent were male and 100% were Caucasian. The mean body mass index (BMI) was 26.1 kg/m2. The mean duration of diabetes was 14.9 years.
The data in Table 2 reflect the exposure of 85 patients with type 2 diabetes to NOVOLOG MIX 70/30 with a mean exposure duration of three months. The mean age was 62.7 years. Fifty-four percent were male and 100% were Caucasian. The mean body mass index (BMI) was 28.1 kg/m2 . The mean duration of diabetes was 15.0 years.
Common adverse reactions were defined as events occurring in ≥5%, excluding hypoglycemia, of the population studied. Common adverse events occurring at the same rate or greater for NOVOLOG MIX 70/30-treated subjects than on comparator-treated subjects during clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus (other than hypoglycemia) are listed in Table 1 and Table 2, respectively. 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.
Table 1: Adverse Reactions Occurring in ≥ 5% of Type 1 Diabetes Mellitus Adult Patients treated with NOVOLOG MIX 70/30 and at the same rate or greater on NOVOLOG MIX 70/30 than on comparator
NOVOLOG MIX 70/30 (N=55) | Novolin 70/30 (N=49) | |||
Preferred Term | N | % | N | % |
Hypoglycemia | 38 | 69 | 37 | 76 |
Headache | 19 | 35 | 6 | 12 |
Influenza-like symptoms | 7 | 13 | 1 | 2 |
Dyspepsia | 5 | 9 | 3 | 6 |
Back pain | 4 | 7 | 2 | 4 |
Diarrhea | 4 | 7 | 3 | 6 |
Pharyngitis | 4 | 7 | 1 | 2 |
Rhinitis | 3 | 5 | 6 | 12 |
Skeletal pain | 3 | 5 | 2 | 4 |
Upper respiratory tract infection | 3 | 5 | 1 | 2 |
Table 2: Adverse reactions Occurring in ≥ 5% of Type 2 Diabetes Mellitus Adult Patients treated with NOVOLOG MIX 70/30and at the same rate or greater on NOVOLOG MIX 70/30 than on comparator
NOVOLOG MIX 70/30 (N=85) | Novolin 70/30 (N=102) | |||
Preferred Term | N | % | N | % |
Hypoglycemia | 40 | 47 | 51 | 50 |
Upper respiratory tract infection | 10 | 12 | 6 | 6 |
Headache | 8 | 9 | 8 | 8 |
Diarrhea | 7 | 8 | 2 | 2 |
Neuropathy | 7 | 8 | 2 | 2 |
Pharyngitis | 5 | 6 | 4 | 4 |
Abdominal pain | 4 | 5 | 0 | 0 |
Rhinitis | 4 | 5 | 2 | 2 |
Severe Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including NOVOLOG MIX 70/30 [see Warnings and Precautions (5.3)]. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for NOVOLOG MIX 70/30 with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice.
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.
The incidence of severe hypoglycemia in adult patients receiving subcutaneous NOVOLOG MIX 70/30 was 16% and 4 % for type 1 and type 2 diabetes patients respectively at 12 weeks [see Clinical Studies (14)].
Allergic Reactions
Patients have experienced reactions such as erythema, edema or pruritus at the site of NOVOLOG MIX 70/30 injection. These reactions usually resolve in a few days to a few weeks, but in some occasions, have required discontinuation of NOVOLOG MIX 70/30. Severe cases of generalized allergy (anaphylaxis) have been reported [see Warnings and Precautions (5.5)].
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, 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 [see Dosage and Administration (2.1)].
Weight gain
Weight gain can occur with some insulin therapies, including NOVOLOG MIX 70/30, and has been attributed to the anabolic effects of insulin and the decrease in glycosuria.
Peripheral Edema
Insulin products, including NOVOLOG MIX 70/30, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to NOVOLOG MIX 70/30 in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
In a 3-month study with an extension in adult subjects with type 2 diabetes, 100% of patients who received NOVOLOG MIX 70/30 were positive for anti-insulin antibodies (AIA) at least once during the first 12 months of the study including 91.4% that were positive at baseline. A total of 91.4% of patients who received NOVOLOG MIX 70/30 were positive for anti-drug antibodies (ADA) at least once during the first 12 months of the study, including 62.1% that were positive at baseline.
In a phase 3 type 2 diabetes clinical trial of NOVOLOG MIX 70/30, initial increase in titers of antibodies to insulin followed by a decrease approaching to baseline values was observed in NOVOLOG MIX 70/30 and Novolin 70/30 treatment groups with similar incidences. These antibodies did not cause deterioration in glycemic control or necessitate increases in insulin dose.
The following adverse reactions have been identified during post-approval use of NOVOLOG MIX 70/30. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Medication errors in which other insulins have been accidentally substituted for NOVOLOG MIX 70/30 have been reported [see Warnings and Precautions (5.4)].
Table 3: Clinically Significant Drug Interactions with NOVOLOG MIX 70/30
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 NOVOLOG MIX 70/30 is co-administered with these drugs. |
Drugs that May Decrease the Blood Glucose Lowering Effect of NOVOLOG MIX 70/30 | |
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 NOVOLOG MIX 70/30 is co-administered with these drugs. |
Drugs that May Increase or Decrease the Blood Glucose Lowering Effect ofNOVOLOG MIX 70/30 | |
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 NOVOLOG MIX 70/30 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 NOVOLOG MIX 70/30 is co-administered with these drugs. |
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) 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. However, subcutaneous reproduction and teratology studies have been performed with NOVOLOG (the rapid-acting component of NOVOLOG MIX 70/30) 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 caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at a dose of 200 units/kg/day (approximately 32-times the human subcutaneous dose of 1.0 units/kg/day, based on units/body surface area), and in rabbits at a dose of 10 units/kg/day (approximately three times the human subcutaneous dose of 1.0 units/kg/day, based on units/body surface area). No significant effects were observed in rats at a dose of 50 units/kg/day and rabbits at a dose of 3 units/kg/day. These doses are approximately 8 times the human subcutaneous dose of 1.0 units/kg/day for rats and equal to the human subcutaneous dose of 1.0 units/kg/day for rabbits based on units/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 in pregnant women.
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 in lactating women. Women with diabetes who are lactating may require adjustments of their insulin doses.
Safety and effectiveness of NOVOLOG MIX 70/30 have not been established in pediatric patients.
Clinical studies of NOVOLOG MIX 70/30 did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. In elderly patients with diabetes, the initial dosing, dose increments should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly.
The effect of renal impairment on the pharmacokinetics of NOVOLOG MIX 70/30 has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent NOVOLOG MIX 70/30 dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.3)].
The effect of hepatic impairment on the pharmacokinetics of NOVOLOG MIX 70/30 has not been studied. Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent NOVOLOG MIX 70/30 dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.3)].
Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.3,5.6)]. 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.
NOVOLOG MIX 70/30 (insulin aspart protamine and insulin aspart injection) is a human insulin analog suspension containing 70% insulin aspart protamine crystals and 30% soluble insulin aspart. NOVOLOG MIX 70/30 is a blood-glucose-lowering agent with an earlier onset and an intermediate duration of action. Insulin aspart is homologous with regular human insulin with the exception of a single substitution of the amino acid proline by aspartic acid in position B28, and is produced by recombinant DNA technology utilizing Saccharomyces cerevisiae (baker’s yeast). Insulin aspart (NOVOLOG) has the empirical formula C256H381N65O79S6 and a molecular weight of 5825.8 Da.
Molecular Chain Of Insulin Aspart. (Image 01)
Figure 1. Structural formula of insulin aspart
NOVOLOG MIX 70/30 is a uniform, white, sterile suspension that contains insulin aspart 100 units/mL.
Inactive ingredients are glycerol 16.0 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 19.6 μg/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL, sodium chloride 0.877 mg/mL, and protamine sulfate 0.32 mg/mL. NOVOLOG MIX 70/30 has a pH of 7.20 - 7.44. Hydrochloric acid or sodium hydroxide may be added to adjust pH.
The primary activity of insulin, including NOVOLOG MIX 70/30 is the regulation of glucose metabolism. Insulin and its analog lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis.
A euglycemic clamp study described below assessed glucose utilization after subcutaneous dosing of NOVOLOG MIX 70/30 in healthy subjects (n = 24). Following a 0.3 units/kg single subcutaneous dose, the onset of action is between 10-20 minutes for NOVOLOG MIX 70/30 compared to 30 minutes for Novolin 70/30. The mean ± SD time to peak activity for NOVOLOG MIX 70/30 is 2.7 hr ± 0.9 hr compared to 4.3 hr ± 3.9 hr for Novolin 70/30. The duration of action may be as long as 24 hours (see Figure 2).
Figure 2. Pharmacodynamic Activity Profile of NOVOLOG MIX 70/30 and Novolin 70/30 in healthy subjects after single 0.3 units/kg subcutaneous dose
The single substitution of the amino acid proline with aspartic acid at position B28 in insulin aspart (NOVOLOG) reduces the molecule’s tendency to form hexamers as observed with regular human insulin. The rapid absorption characteristics of NOVOLOG are maintained by NOVOLOG MIX 70/30.
Absorption and Bioavailability
The 30% insulin aspart in the soluble component of NOVOLOG MIX 70/30 is absorbed more rapidly from the subcutaneous layer than regular human insulin. The remaining 70% is in crystalline form as insulin aspart protamine which has a prolonged absorption profile after subcutaneous injection.
The relative bioavailability of NOVOLOG MIX 70/30 compared to NOVOLOG and Novolin 70/30 indicates that the insulins are absorbed to similar extent. In a euglycemic clamp study in healthy subjects (n=24) after dosing with NOVOLOG MIX 70/30 (0.3 units/kg), a mean maximum serum concentration (Cmax) of 61.3 ± 20.1 milliunits/L was reached after 85 minutes. Serum insulin levels returned to baseline 16 to 20 hours after a subcutaneous dose of NOVOLOG MIX 70/30 (see Fig. 3 for pharmacokinetic profiles).
Figure 3. Pharmacokinetic Profiles of NOVOLOG MIX 70/30 and Novolin 70/30 after single 0.3 units/kg subcutaneous dose
Distribution and Elimination
Insulin aspart has a low binding affinity to plasma proteins (<10%), similar to that seen with regular human insulin.
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of NOVOLOG MIX 70/30. In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with NOVOLOG, the rapid-acting component of NOVOLOG MIX 70/30, at 10, 50, and 200 units/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of 1.0 unit/kg/day, based on units/body surface area, respectively). At a dose of 200 units/kg/day, NOVOLOG increased the incidence of mammary gland tumors in females when compared to untreated controls. 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 units/kg/day (approximately 32 times the human subcutaneous dose, based on units/body surface area) had no direct adverse effects on male and female fertility, or on general reproductive performance of animals.
In standard biological assays in mice and rabbits, one unit of NOVOLOG has the same glucose-lowering effect as one unit of regular human insulin.
In a three-month, open-label trial, patients with type 1 (n=104) or type 2 (n=187) diabetes were treated twice daily (before breakfast and before supper) with NOVOLOG MIX 70/30 or Novolin 70/30. Patients had received insulin for at least 24 months before the study. Oral hypoglycemic agents were not allowed within 1 month prior to the study or during the study. The small changes in HbA1c were comparable across the treatment groups (see Table 4).
The mean age of the trial population for type 1 was 43.2 years and 62.7 for type 2. For type 1, 64% were male and for type 2, 54% were male and 100% were Caucasian for type 1 and type 2. The mean body mass index (BMI) was 26.1 kg/m2 for type 1 and 28.1 kg/m2 for type 2. The mean duration of diabetes was 14.9 years for type 1 and 15.0 years for type 2.
Table 4: Glycemic Parameters at the End of Treatment [Mean ± SD (N subjects)]
NOVOLOG MIX 70/30 | Novolin 70/30 | |
Type 1, N=104 | ||
Fasting Blood Glucose (mg/dL) | 174 ± 64 (48) | 142 ± 59 (44) |
1.5 Hour Post Breakfast (mg/dL) | 187 ± 82 (48) | 200 ± 82 (42) |
1.5 Hour Post Dinner (mg/dL) | 162 ± 77 (47) | 171 ± 66 (41) |
HbA1c (%) Baseline | 8.4 ± 1.2 (51) | 8.5 ± 1.1 (46) |
HbA1c (%) Week 12 | 8.4 ± 1.1 (51) | 8.3 ± 1.0 (47) |
Type 2, N=187 | ||
Fasting Blood Glucose (mg/dL) | 153 ± 40 (76) | 152 ± 69 (93) |
1.5 Hour Post Breakfast (mg/dL) | 182 ± 65 (75) | 200 ± 80 (92) |
1.5 Hour Post Dinner (mg/dL) | 168 ± 51 (75) | 191 ± 65 (93) |
HbA1c (%) Baseline | 8.1 ± 1.2 (82) | 8.2 ± 1.3 (98) |
HbA1c (%) Week 12 | 7.9 ± 1.0 (81) | 8.1 ± 1.1 (96) |
The significance, with respect to the long-term clinical sequelae of diabetes, of the differences in postprandial hyperglycemia between treatment groups has not been established.
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.
Trial 1:
In a 34-week, open-label trial, insulin-naïve patients with type 2 diabetes currently treated with 2 oral antidiabetic agents were switched to treatment with metformin and pioglitazone. The mean age of the trial population was 53.4 years and mean duration of diabetes was 9.2 years. Forty-six percent were male. Eighty-five percent were White, 12% were Black and 3% were Asian. The mean BMI was approximately 32.4 kg/m2. During an 8-week optimization period metformin and pioglitazone were increased to 2500 mg per day and 30 or 45 mg per day, respectively. After the optimization period, subjects were randomized to receive either NOVOLOG MIX 70/30 twice daily added on to the metformin and pioglitazone regimen or continue the current optimized metformin and pioglitazone therapy. NOVOLOG MIX 70/30 was started at a dose of 6 IU twice daily (before breakfast and before supper). Insulin doses were titrated to a pre-meal glucose goal of 80-110 mg/dL. The total daily insulin dose at the end of the study was 56.9 ± 30.5 IU.
Table 5: Combination Therapy with Oral Agents and Insulin in Patients with Type 2 Diabetes Mellitus [Mean (SD)]
Treatment duration 24-weeks | NOVOLOG MIX 70/30 + Metformin + Pioglitazone | Metformin + Pioglitazone |
HbA1c | ||
Baseline mean ± SD (n) | 8.1 ± 1.0 (102) | 8.1 ± 1.0 (98) |
End-of-study mean ± SD (n) - LOCF | 6.6 ± 1.0 (93) | 7.8 ± 1.2 (87) |
Adjusted Mean change from baseline ± SE (n)* | -1.6 ± 0.1 (93) | -0.3 ± 0.1 (87) |
Treatment difference mean ± SE* 95% CI* | -1.3 ± 0.1 (-1.6, -1.0) | |
Percentage of subjects reaching HbA1c <7.0% | 76% | 24% |
Percentage of subjects reaching HbA1c ≤6.5% | 59% | 12% |
Fasting Blood Glucose (mg/dL) | ||
Baseline Mean ± SD (n) | 173 ± 39.8 (93) | 163 ± 35.4 (88) |
End of Study Mean ± SD (n) - LOCF | 130 ± 50.0 (90) | 162 ± 40.8 (84) |
Adjusted Mean change from baseline ± SE (n)* | -43.0 ± 5.3 (90) | -3.9 ± 5.3 (84) |
End-of-Study Blood Glucose (Plasma) (mg/dL) | ||
2 Hour Post Breakfast | 138 ± 42.8 (86) | 188 ± 57.7 (74) |
2 Hour Post Lunch | 150 ± 41.5 (86) | 176 ± 56.5 (74) |
2 Hour Post Dinner | 141 ± 57.8 (86) | 195 ± 60.1 (74) |
Table 6: Combination Therapy with Oral Agents and Two Types of Insulin in Patients with Type 2 Diabetes Mellitus [Mean (SD)]
Treatment duration 28-weeks | NOVOLOG MIX 70/30 + Metformin ± Pioglitazone | Insulin Glargine + Metformin ± Pioglitazone |
Number of patients | 117 | 116 |
HbA1c | ||
Baseline mean (%) | 9.7 ± 1.5 (117) | 9.8 ± 1.4 (114) |
End-of-study mean (± SD) | 6.9 ± 1.2 (108) | 7.4 ± 1.2 (114) |
Mean change from baseline | -2.7 ± 1.6 (108) | -2.4 ± 1.5 (114) |
Percentage of subjects reaching HbA1c <7.0% | 66% | 40% |
NOVOLOG MIX 70/30 100 units per mL (U-100), 70% insulin aspart protamine and 30% insulin aspart, is available as a white and cloudy injectable suspension:
10 mL vials | NDC 0169-3685-12 |
3 mL NOVOLOG MIX 70/30 FlexPen | NDC 0169-3696-19 |
Unused NOVOLOG MIX 70/30 should be stored in a refrigerator between 2°C and 8°C (36°F to 46°F). Do not freeze NOVOLOG MIX 70/30 or use NOVOLOG MIX 70/30 if it has been frozen. Do not expose NOVOLOG to excessive heat or light.
Always remove the needle after each injection and store NOVOLOG MIX 70/30 FlexPen without a needle attached. This prevents contamination and/or infection, or leakage of insulin, and will ensure accurate dosing. Always use a new needle for each injection to prevent contamination.
The storage conditions are summarized in the following table:
Table 7:Storage conditions for NOVOLOG MIX 70/30 vial and FlexPen
Not in-use (unopened) Room Temperature (below 30°C [86°F]) | Not in-use (unopened) Refrigerated (2°C - 8°C [36°F - 46°F]) | In-use (opened) Room Temperature (below 30°C [86°F]) | |
10 mL vial | 28 days | Until expiration date | 28 days (refrigerated/room temperature) |
3 mL NOVOLOG MIX 70/30 FlexPen | 14 days | Until expiration date | 14 days (Do not refrigerate) |
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Never Share a NOVOLOG MIX 70/30 FlexPen between Patients
Advise patients that they must never share NOVOLOG MIX 70/30 FlexPen device with another person even if the needle is changed. Advise patients using NOVOLOG MIX 70/30 vials not to share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)].
Hypoglycemia
Inform patients that hypoglycemia is the most common adverse reaction with insulin. Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of NOVOLOG MIX 70/30 therapy. Instruct patients on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals. Instruct patients on the management of hypoglycemia [see Warnings and Precautions (5.3)].
Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery.
Hypoglycemia with Medication Errors
Instruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products [see Warnings and Precautions (5.4)].
Hypersensitivity Reactions
Advise patients that hypersensitivity reactions have occurred with NOVOLOG MIX 70/30. Inform patients of the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.5)].
Women of Reproductive Potential
Advise patients to inform their health care professional if they are pregnant or are contemplating pregnancy.
Administration
Version: 14
Novo Nordisk®, NOVOLOG®, FlexPen®, and Novolin® are registered trademarks of Novo Nordisk® A/S.
Patent Information: http://novonordisk-us.com/patients/products/product-patents.html
© 2002 – 2017 Novo Nordisk
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
For information about NOVOLOG MIX 70/30 contact:
Novo Nordisk Inc.
800 Scudders Mill Road
Plainsboro, New Jersey 08536
1-800-727-6500
www.novonordisk-us.com
NovoLog® Mix 70/30 (NŌ-vō-log-MIX-SEV-en-tee-THIR-tee)
(insulin aspart protamine and insulin aspart injectable suspension)
Do not share your NovoLog Mix 70/30 FlexPen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them.
What is NovoLog Mix 70/30?
Who should not take NovoLog Mix 70/30?
Do not take NovoLog Mix 70/30 if you:
Before taking NovoLog Mix 70/30, tell your healthcare provider about all your medical conditions including, if you are:
Before you start taking NovoLog Mix 70/30, talk to your healthcare provider about low blood sugar and how to manage it.
How should I take NovoLog Mix 70/30?
What should I avoid while taking NovoLog Mix 70/30?
While taking NovoLog Mix 70/30 do not:
What are the possible side effects of NovoLog Mix 70/30?
NovoLog Mix 70/30 may cause serious side effects that can lead to death, including:
Low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include:
Your insulin dose may need to change because of:
Other common side effects of NovoLog Mix 70/30 may include:
Get emergency medical help if you have:
These are not all the possible side effects of NovoLog Mix 70/30. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of NovoLog Mix 70/30.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about NovoLog Mix 70/30 that is written for health professionals. Do not use NovoLog Mix 70/30 for a condition for which it was not prescribed. Do not give NovoLog Mix 70/30 to other people, even if they have the same symptoms that you have. It may harm them.
What are the ingredients in NovoLog Mix 70/30?
Active Ingredient: 70% insulin aspart protamine and 30% insulin aspart.
Inactive Ingredients: glycerol, phenol, metacresol, zinc, disodium hydrogen phosphate dihydrate, sodium chloride, protamine sulfate, water for injection, hydrochloric acid or sodium hydroxide.
Manufactured by: Novo Nordisk A/S; DK-2880 Bagsvaerd, Denmark
For more information, go to www.novonordisk-us.com or call 1-800-727-6500.
This Patient Information has been approved by the U.S. Food and Drug Administration
Revised: 05/2017
INSTRUCTIONS FOR USE
NovoLog® Mix 70/30 (NŌ-vō-Log-MIX-SEV-en-tee-THIR-tee)
(insulin aspart protamine and insulin aspart injectable suspension)
10 mL vial (100 Units/mL, U-100)
Read this Instructions for Use before you start taking NovoLog® Mix 70/30 and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
Supplies you will need to give your NovoLog® Mix 70/30 injection:
Vial Figure (Image 35)
Preparing your NovoLog® Mix 70/30 dose:
Hand & Vial Figure (Image 36)
Step 1: If you are using a new vial, pull off the tamper-resistant cap (See Figure A).
Step 2: Wipe the rubber stopper with an alcohol swab (See Figure B).
Figure A & Figure B (Image 37)
Step 3: Roll the NovoLog Mix 70/30 vial between your hands 10 times. Keep the vial in a horizontal (flat) position (See Figure C). Roll the vial between your hands until the NovoLog® Mix 70/30 looks white and cloudy. Do not shake the vial.
Figure C (Image 38)
Step 4: Hold the syringe with the needle pointing up. Pull down on the plunger until the black tip reaches the line for the number of units for your prescribed dose (See Figure D).
Figure D (Image 39)
Step 5: Push the needle through the rubber stopper of the NovoLog® Mix 70/30 vial (See Figure E).
Figure E (Image 40)
Step 6: Push the plunger all the way in. This puts air into the NovoLog® Mix 70/30 vial (See Figure F).
Figure F (Image 41)
Step 7: Turn the NovoLog® Mix 70/30 vial and syringe upside down and slowly pull the plunger down until the black tip is a few units past the line for your dose (See Figure G).
Figure G (Image 42)
Figure H (Image 43)
Step 8: Slowly push the plunger up until the black tip reaches the line for your NovoLog® Mix 70/30 dose (See Figure I).
Figure I (Image 44)
Step 9: Check the syringe to make sure you have the right dose of NovoLog® Mix 70/30.
Step 10: Pull the syringe out of the vial’s rubber stopper (See Figure J).
Figure J (Image 45)
Giving your injection:
Step 11: Choose your injection site and wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose (See Figure K).
Step 12: Insert the needle into your skin. Push down on the plunger to inject your dose (See Figure L). Needle should remain in the skin for at least 6 seconds to make sure you have injected all the insulin.
Figure L (Image 47)
Step 13: Pull the needle out of your skin. After that, you may see a drop of NovoLog® Mix 70/30 at the needle tip. This is normal and does not affect the dose you just received (See Figure M).
Figure M (Image 48)
After your injection:
How should I store NovoLog® Mix 70/30?
General information about the safe and effective use of NovoLog® Mix 70/30
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Manufactured by:
Novo Nordisk A/S
DK-2880 Bagsvaerd, Denmark
Revised: May 2017
NovoLog® is a registered trademark of Novo Nordisk A/S.
PATENT Information: http://novonordisk-us.com/patients/products/product-patents.html
© 2002-2017 Novo Nordisk
For information about NovoLog® Mix 70/30 contact:
Novo Nordisk Inc.
800 Scudders Mill Road
Plainsboro, New Jersey 08536
1-800-727-6500
www.novonordisk-us.com
INSTRUCTIONS FOR USE
NovoLog® Mix 70/30 FlexPen®
Read the following instructions carefully before you start using your NovoLog® Mix 70/30 FlexPen® and each time you get a refill. There may be new information. You should read the instructions even if you have used NovoLog Mix 70/30 FlexPen before.
Do not share your NovoLog Mix 70/30 FlexPen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them.
NovoLog Mix 70/30 FlexPen is a disposable dial-a-dose insulin pen. You can select doses from 1 to 60 units in increments of 1 unit. NovoLog Mix 70/30 FlexPen is designed to be used with NovoFine®, NovoFine® Plus or NovoTwist® needles.
NovoLog Mix 70/30 FlexPen should not be used by people who are blind or have severe visual problems without the help of a person who has good eyesight and who is trained to use the NovoLog Mix 70/30 FlexPen the right way.
Getting ready
Make sure you have the following items:
Flexpen Drawing (Image 04)
Preparing your NovoLog Mix 70/30 FlexPen
Before your first injection with a new NovoLog Mix 70/30 FlexPen you must mix the insulin:
A. Let the insulin reach room temperature before you use it. This makes it easier to mix.
Pull off the pen cap (see diagram A).
Pull Off The Pen Cap. (Image 50)
B. Roll the pen between your palms 10 times - it is important that the pen is kept horizontal (see diagram B).
Roll The Pen Between Your Palms. (Image 51)
C. Then gently move the pen up and down ten times between position 1 and 2 as shown, so the glass ball moves from one end of the cartridge to the other (see diagram C).
Move The Pen Up And Down. (Image 52)
Repeat rolling and moving the pen until the liquid appears white and cloudy.
For every following injection move the pen up and down between positions 1 and 2 at least ten times until the liquid appears white and cloudy.
After mixing, complete all the following steps of the injection right away. If there is a delay, the insulin will need to be mixed again.
Wipe the rubber stopper with an alcohol swab.
Δ Before you inject, there must be at least 12 units of insulin left in the cartridge to make sure the remaining insulin is evenly mixed. If there are less than 12 units left, use a new NovoLog Mix 70/30 FlexPen.
Attaching the needle
D. Remove the protective tab from a disposable needle.
Screw the needle tightly onto your NovoLog Mix 70/30 FlexPen. It is important that the needle is put on straight (see diagram D).
Never place a disposable needle on your NovoLog Mix 70/30 FlexPen until you are ready to take your injection.
Figure D (Image 05)
E. Pull off the big outer needle cap (see diagram E).
F. Pull off the inner needle cap and dispose of it (see diagram F).
Figure F (Image 06)
Δ Be careful not to bend or damage the needle before use.
Δ To reduce the risk of a needle stick, never put the inner needle cap back on the needle.
Giving the airshot before each injection
Before each injection small amounts of air may collect in the cartridge during normal use. To avoid injecting air and to make sure you take the right dose of insulin:
G. Turn the dose selector to select 2 units (see diagram G).
Turn The Dose Selector To 2 Units. (Image 56)
H. Hold your NovoLog Mix 70/30 FlexPen with the needle pointing up. Tap the cartridge gently with your finger a few times to make any air bubbles collect at the top of the cartridge (see diagram H).
Tap The Needle. (Image 57)
I. Keep the needle pointing upwards, press the push-button all the way in (see diagram I). The dose selector returns to 0.
Press The Push-button. (Image 58)
A drop of insulin should appear at the needle tip. If not, change the needle and repeat the procedure no more than 6 times.
If you do not see a drop of insulin after 6 times, do not use the NovoLog Mix 70/30 FlexPen and contact Novo Nordisk at 1-800-727-6500.
A small air bubble may remain at the needle tip, but it will not be injected.
Selecting your dose
Check and make sure that the dose selector is set at 0.
J. Turn the dose selector to the number of units you need to inject. The pointer should line up with your dose.
The dose can be corrected either up or down by turning the dose selector in either direction until the correct dose lines up with the pointer (see diagram J). When turning the dose selector, be careful not to press the push-button as insulin will come out.
You cannot select a dose larger than the number of units left in the cartridge.
You will hear a click for every single unit dialed. Do not set the dose by counting the number of clicks you hear.
Select Your Dose. (Image 59)
Δ Do not use the cartridge scale printed on the cartridge to measure your dose of insulin.
Giving the injection
K. Insert the needle into your skin.
Inject the dose by pressing the push-button all the way in until the 0 lines up with the pointer (see diagram K). Be careful only to push the button when injecting.
Turning the dose selector will not inject insulin.
Press The Push Button To Inject. (Image 60)
L. Keep the needle in the skin for at least 6 seconds, and keep the push-button pressed all the way in until the needle has been pulled out from the skin (see diagram L). This will make sure that the full dose has been given.
Keep The Needle In The Skin For At Least 6 Seconds. (Image 61)
You may see a drop of insulin at the needle tip. This is normal and has no effect on the dose you just received. If blood appears after you take the needle out of your skin, press the injection site lightly with an alcohol swab. Do not rub the area.
After the injection
Do not recap the needle. Recapping can lead to a needle stick injury. Remove the needle from the NovoLog Mix 70/30 FlexPen after each injection and dispose of it. This helps to prevent infection, leakage of insulin, and will help to make sure you inject the right dose of insulin. If you do not have a sharps container, carefully slip the needle into the outer needle cap. Safely remove the needle and throw it away as soon as you can.
Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.
The NovoLog Mix 70/30 FlexPen prevents the cartridge from being completely emptied. It is designed to deliver 300 units.
M. Put the pen cap on the NovoLog Mix 70/30 FlexPen and store the NovoLog Mix 70/30 FlexPen without the needle attached (see diagram M). Storing without the needle attached helps prevent leaking, blocking of the needle, and air from entering the Pen.
Replace The Pen Cap. (Image 62)
How should I store NovoLog Mix 70/30 FlexPen?
Maintenance
For the safe and proper use of your NovoLog Mix 70/30 FlexPen be sure to handle it with care. Avoid dropping your NovoLog Mix 70/30 FlexPen as it may damage it. If you are concerned that your NovoLog Mix 70/30 FlexPen is damaged, use a new one. You can clean the outside of your NovoLog Mix 70/30 FlexPen by wiping it with a damp cloth. Do not soak or wash your NovoLog Mix 70/30 FlexPen as it may damage it. Do not refill your NovoLog Mix 70/30 FlexPen.
Δ Remove the needle from the NovoLog Mix 70/30 FlexPen after each injection. This helps to ensure sterility, prevent leakage of insulin, and will help to make sure you inject the right dose of insulin for future injections.
Δ Be careful when handling used needles to avoid needle sticks and transfer of infectious diseases.
Δ Keep your NovoLog Mix 70/30 FlexPen and needles out of the reach of children.
Δ Use NovoLog Mix 70/30 FlexPen as directed to treat your diabetes.
Δ Do not share your NovoLog Mix 70/30 FlexPen or needles with other people. You may give other people a serious infection, or get a serious infection from them.
Δ Always use a new needle for each injection.
Δ Novo Nordisk is not responsible for harm due to using this insulin pen with products not recommended by Novo Nordisk.
Δ As a precautionary measure, always carry a spare insulin delivery device in case your NovoLog Mix 70/30 FlexPen is lost or damaged.
Δ Remember to keep the disposable NovoLog Mix 70/30 FlexPen with you. Do not leave it in a car or other location where it can get too hot or too cold.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Revised: 04/2015
NovoLog® Mix 70/30
NDC 0169-3685-12
List 368512
insulin aspart protamine
and insulin aspart injectable suspension
100 units/mL 10 mL
Shake carefully before using. See enclosed insert for proper technique.
Rx only
U-100
novo nordisk®
NDC 0169-3696-19
List 369619
NovoLog® Mix 70/30
FlexPen® Prefilled Syringe
insulin aspart protamine and
insulin aspart injectable suspension
For Single Patient Use Only
100 units/mL (U-100)
5x3 mL Prefilled insulin Syringes
Shake carefully before using.
See enclosed insert for proper technique.
Rx only
For use with NovoFine®,
NovoFine® Plus or NovoTwist®
disposable needles.
Keep in a cold place.
Avoid freezing.
Protect from light.
novo nordisk®
* Please review the disclaimer below.
