insulin aspart protamine / insulin aspart 70/30 in 3 ML Pen Injector
Generic Name: INSULIN ASPART
Brand Name: NovoLog Mix 70/30
- Substance Name(s):
- INSULIN ASPART
DRUG INTERACTIONS
7 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 of NOVOLOG 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.
• Drugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics (7) .
• Drugs that may decrease the blood glucose lowering effect: atypical antipsychotics, 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 (7) .
• Drugs that may increase or decrease the blood glucose lowering effect: a lcohol, beta-blockers, clonidine, lithium salts, and pentamidine (7) .
• Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine (7) .
OVERDOSAGE
10 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.
DESCRIPTION
11 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 C 256 H 381 N 65 O 79 S 6 and a molecular weight of 5825.8 Da.
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.
Molecular chain of insulin aspart.
CLINICAL STUDIES
14 14.1 Clinical Studies in Adult Patients with Type 1 and Type 2 Diabetes 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 HbA 1c 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/m 2 for type 1 and 28.1 kg/m 2 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) HbA 1c (%) Baseline 8.4 ± 1.2 (51) 8.5 ± 1.1 (46) HbA 1c (%) 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) HbA 1c (%) Baseline 8.1 ± 1.2 (82) 8.2 ± 1.3 (98) HbA 1c (%) 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.
14.2 Clinical Studies in Adult Patients with Type 2 Diabetes with Insulin and Oral Antidiabetic Agents 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/m 2 .
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 HbA 1c 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 HbA 1c <7.0% 76% 24% Percentage of subjects reaching HbA 1c ≤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) *Adjusted mean per group, treatment difference, and 95% CI were obtained based on an ANCOVA model with treatment, FPG stratum, and secretagogue stratum as fixed factors and baseline HbA 1c as the covariate.
Trial 2: In a 28-week, open-label trial, insulin-naïve patients with type 2 diabetes with fasting plasma glucose above 140 mg/dL currently treated with metformin ± thiazolidinedione therapy were randomized to receive either NOVOLOG MIX 70/30 twice daily [before breakfast and before supper] or insulin glargine once daily (see Table 6).
NOVOLOG MIX 70/30 was started at an average dose of 5-6 IU (0.07 ± 0.03 IU/kg) twice daily (before breakfast and before supper), and bedtime insulin glargine was started at 10-12 IU (0.13 ± 0.03 IU/kg).
Insulin doses were titrated weekly by decrements or increments of -2 to +6 units per injection to a pre-meal glucose goal of 80-110 mg/dL.
The metformin dose was adjusted to 2550 mg/day.
Approximately one-third of the patients in each group were also treated with pioglitazone (30 mg/day).
Insulin secretagogues were discontinued in order to reduce the risk of hypoglycemia.
Most patients were Caucasian (53%), and the mean initial weight was 90 kg.
The mean age of the trial population was 52.6 years and mean duration of diabetes was 9.5 years.
Fifty three percent were male.
Fifty-five percent were Caucasian, 15% Black, 27% were Hispanic, 2% were Asian and 2% were Other.
The mean BMI was approximately 31.5 kg/m 2 .
Table 6: C ombination 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 HbA 1c 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 HbA 1c <7.0% 66% 40%
HOW SUPPLIED
16 /STORAGE AND HANDLING 16.1 How Supplied 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 multiple-dose vial NDC 0169-3685-12 3 mL single-patient-use NOVOLOG MIX 70/30 FlexPen NDC 0169-3696-19 The NOVOLOG MIX 70/30 FlexPen dials in 1-unit increments.
16.2 Recommended Storage Dispense in the original sealed carton with the enclosed Instructions for Use.
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 MIX 70/30 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 multiple-dose vial 28 days Until expiration date 28 days (refrigerated/room temperature) 3 mL single-patient-use NOVOLOG MIX 70/30 FlexPen 14 days Until expiration date 14 days (Do not refrigerate)
RECENT MAJOR CHANGES
Dosage and Administration (2.1)…………………………… 11/2019 Dosage and Administration (2.2)…………………………….12/2018 Warnings and Precautions (5.2)……………………………..
11/2019
GERIATRIC USE
8.5 Geriatric Use 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.
DOSAGE FORMS AND STRENGTHS
3 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: • 10 mL multiple-dose vial • 3 mL single-patient-use NOVOLOG MIX 70/30 FlexPen Injectable suspension: NOVOLOG MIX 70/30 is 100 units per mL (U-100), 70% insulin aspart protamine and 30% insulin aspart, is available as: (3) • 10 mL multiple-dose vial • 3 mL single-patient-use NOVOLOG MIX 70/30 FlexPen
MECHANISM OF ACTION
12.1 Mechanism of Action 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.
INDICATIONS AND USAGE
1 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 not recommended for the treatment of diabetic ketoacidosis.
• The proportions of rapid-acting and long-acting insulins in NOVOLOG MIX 70/30 are fixed and do not allow for basal versus prandial dose adjustments.
NOVOLOG MIX 70/30 is a mixture of insulin aspart protamine, an intermediate-acting human insulin analog, and insulin aspart, a rapid-acting human insulin analog, indicated to improve glycemic control in patients with diabetes mellitus.
Limitations of Use: • Not recommended for the treatment of diabetic ketoacidosis.
• The proportions of rapid-acting and long-acting insulins are fixed and do not allow for basal versus prandial dose adjustments (1) .
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness of NOVOLOG MIX 70/30 have not been established in pediatric patients.
PREGNANCY
8.1 Pregnancy Risk Summary There are no available data with NOVOLOG MIX 70/30 in pregnant women to inform a drug-associated risk for major birth defects and miscarriage.
Available information from published randomized controlled trials with insulin aspart use during the second trimester of pregnancy have not reported an association with insulin aspart and major birth defects or adverse maternal or fetal outcomes [see Data] .
There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations] .
In animal reproduction studies, administration of subcutaneous insulin aspart to pregnant rats and rabbits during the period of organogenesis did not cause adverse developmental effects at exposures 8-times and equal to the human subcutaneous dose of 1 unit/kg/day, respectively.
Pre- and post-implantation losses and visceral/skeletal abnormalities were seen at higher exposures, which are considered secondary to maternal hypoglycemia.
These effects were similar to those observed in rats administered regular human insulin [see Data] .
The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA 1c >7% and has been reported to be as high as 20-25% in women with a HbA 1c >10%.
The estimated background risk of miscarriage for the indicated population is unknown.
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications.
Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.
Data Human Data Published data from 5 randomized controlled trials of 441 pregnant women with diabetes mellitus treated with insulin aspart during the late 2 nd trimester of pregnancy did not identify an association of insulin aspart with major birth defects or adverse maternal or fetal outcomes.
However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including a variable duration of treatment and small size of the majority of the trials.
Animal Data Fertility, embryo-fetal and pre- and postnatal development studies have been performed with insulin aspart and regular human insulin in rats and rabbits.
In a combined fertility and embryo-fetal development study in rats, insulin aspart was administered before mating, during mating, and throughout pregnancy.
Further, in a pre- and postnatal development study insulin aspart was given throughout pregnancy and during lactation to rats.
In an embryo-fetal development study insulin aspart was given to female rabbits during organogenesis.
The effects of insulin aspart did not differ from those observed with subcutaneous regular human insulin.
Insulin aspart, like human insulin, 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 unit/kg/day, based on human exposure equivalents) and in rabbits at a dose of 10 units/kg/day (approximately three times the human subcutaneous dose of 1 unit/kg/day, based on human exposure equivalents).
No significant effects were observed in rats at a dose of 50 units/kg/day and in rabbits at a dose of 3 units/kg/day.
These doses are approximately 8 times the human subcutaneous dose of 1 unit/kg/day for rats and equal to the human subcutaneous dose of 1 unit/kg/day for rabbits, based on human exposure equivalents.
The effects are considered secondary to maternal hypoglycemia.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS • Never share a NOVOLOG MIX 70/30 FlexPen 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 glucose monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; and in patients with renal or hepatic impairments and hypoglycemia unawareness (5.3) .
• 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, may occur.
Discontinue NOVOLOG MIX 70/30, treat, and monitor, if indicated (5.5) .
• Hypokalemia: May be life-threatening.
Monitor potassium levels in patients at risk of 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 NOVOLOG MIX 70/30 FlexPen Between Patients 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.
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 ( 6.1 , 6.3 )] .
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 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.
5.4 Hypoglycemia Due to Medication Errors 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.
5.5 Hypersensitivity and Allergic Reactions 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)] .
5.6 Hypokalemia 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).
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, 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION 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)] .
Hyperglycemia or 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.
Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions ( 5.2 )] .
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)] .
Administration • Advise patients to inspect NOVOLOG MIX 70/30 visually before use.
It should appear uniformly white and cloudy.
Instruct them to not use it if it looks clear or contains solid particles.
• NOVOLOG MIX 70/30 must be resuspended immediately before use.
Resuspension is easier when the insulin has reached room temperature.
• Instruct patients when using the vial, to roll the vial gently in their hands in a horizontal position 10 times until the suspension appears uniformly white and cloudy.
The patient should use immediately after resuspension.
• Instruct patients when using NOVOLOG MIX 70/30 FlexPen, to roll NOVOLOG MIX 70/30 FlexPen gently between their hands in a horizontal position 10 times.
Then, to turn NOVOLOG MIX 70/30 FlexPen upside down so that the glass ball moves from one end of the reservoir to the other 10 times until the suspension appears uniformly white and cloudy.
The patient should use immediately after resuspension.
• Instruct patients to administer NOVOLOG MIX 70/30 by subcutaneous injection in the abdominal region, buttocks, thigh, or upper arm and to rotate injection sites within the same region to reduce the risk of lipodystrophy.
Version: 16 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 – 2019 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
DOSAGE AND ADMINISTRATION
2 • Inject NOVOLOG MIX 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm (2.1).
• Administer the dose within 15 minutes before meal initiation.
For patients with type 2 diabetes, the dose may also be given after meal initiation ( 2.1 ).
• Rotate injection sites within the same region from one injection to the next to reduce risk of lipodystrophy and localized cutaneous amyloidosis (2.1) .
• Inspect visually before use.
Appearance should be uniformly white and cloudy.
Do not use it if it looks clear or if it contains solid particles (2.1) .
• NOVOLOG MIX 70/30 must be resuspended immediately before use.
Resuspension is easier when the insulin has reached room temperature ( 2.1 ).
• Do not administer intravenously or use in insulin infusion pumps ( 2.1 ).
• NOVOLOG MIX 70/30 is typically dosed twice-daily (with each dose intended to cover 2 meals or a meal and a snack) (2.2) .
• Individualize dosage based on metabolic needs, blood glucose monitoring results, glycemic control goal ( 2.2 ).
• 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 ( 2.2 ).
• Dosage adjustment may be needed when switching from another insulin to NOVOLOG MIX 70/30 ( 2.2 ).
2.1 Important Administration Information • Always check insulin labels before administration [see Warnings and Precautions (5.4)] .
• Inject NOVOLOG MIX 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm.
• Administer the dose within 15 minutes before meal initiation.
For patients with type 2 diabetes, the dose may also be given after meal initiation.
• Rotate injection sites 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 ) and Adverse Reactions ( 6.1, 6.3 )].
• During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )].
• Inspect NOVOLOG MIX 70/30 visually before use.
It should appear uniformly white and cloudy.
Do not use it if it looks clear or if it contains solid particles.
• NOVOLOG MIX 70/30 must be resuspended immediately before use.
Resuspension is easier when the insulin has reached room temperature.
• When using the vial, roll the vial gently in hands in a horizontal position 10 times until the suspension appears uniformly white and cloudy.
Inject immediately.
• When using NOVOLOG MIX 70/30 FlexPen, roll NOVOLOG MIX 70/30 FlexPen gently between hands in a horizontal position 10 times.
Then, turn NOVOLOG MIX 70/30 FlexPen upside down so that the glass ball moves from one end of the reservoir to the other 10 times until the suspension appears uniformly white and cloudy.
Inject immediately.
• The NOVOLOG MIX 70/30 FlexPen dials in 1-unit increments.
• Use NOVOLOG MIX 70/30 FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
• Do not administer NOVOLOG MIX 70/30 intravenously or use in insulin infusion pumps.
• Do not mix NOVOLOG MIX 70/30 with any other insulins.
2.2 Dosage Information • NOVOLOG MIX 70/30 is typically dosed twice-daily (with each dose intended to cover 2 meals or a meal and a snack).
• Individualize and adjust the dosage of NOVOLOG MIX 70/30 based on the individual’s metabolic needs, blood glucose monitoring results and glycemic control goal.
• 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 (5.3) and Use in Specific Populations (8.6, 8.7)] .
• Dosage adjustment may be needed when switching from another insulin to NOVOLOG MIX 70/30 [see Warnings and Precautions (5.2)] .
2.3 Dosage Adjustment Due to Drug Interactions • Dosage adjustment may be needed when NOVOLOG MIX 70/30 is co-administered with certain drugs [see Drug Interactions (7)] .