AFREZZA® is a rapid acting inhaled human insulin indicated to improve glycemic control in adult patients with diabetes mellitus.

{ "type": "p", "children": [], "text": "AFREZZA® is a rapid acting inhaled human insulin indicated to improve glycemic control in adult patients with diabetes mellitus.\n" }

Limitations of Use:

{ "type": "p", "children": [], "text": "\nLimitations of Use:\n" }

{ "type": "ul", "children": [ "AFREZZA is not recommended for the treatment of diabetic ketoacidosis [see Warning and Precautions (5.6)].\n", "The safety and effectiveness of AFREZZA in patients who smoke have not been established. The use of AFREZZA is not recommended in patients who smoke or who have recently stopped smoking.\n" ], "text": "" }

AFREZZA is contraindicated in patients with chronic lung disease because of the risk of acute bronchospasm in these patients. Before initiating AFREZZA, perform a medical history, physical examination and spirometry (FEV1) in all patients to identify potential lung disease [see Contraindications (4) and Warnings and Precautions (5.1)].

Only administer AFREZZA via oral inhalation using the AFREZZA Inhaler. Administer AFREZZA at the beginning of each meal. Administer AFREZZA using a single inhalation per cartridge (if the dose is greater than the contents of a single cartridge, more than one cartridge is needed) [see Dosage and Administration (2.3)]. For additional administration instructions on how to use the AFREZZA Inhaler [see Dosage and Administration (2.6)] and see the Instructions for Use.

The AFREZZA Inhaler can be used for up to 15 days from the date of first use. After 15 days of use, the inhaler must be discarded and replaced with a new inhaler.

For insulin naïve patients, start on 4 units of AFREZZA at the beginning of each meal.

For patients using subcutaneous, mealtime (prandial) insulin:

For patients using subcutaneous, pre-mixed insulin:

For AFREZZA doses exceeding the contents of a single cartridge at mealtime, inhalations from more than one cartridge are necessary. To achieve the required total mealtime dose, use a combination of 4 unit, 8 unit, and 12 unit cartridges. Examples of cartridge combinations for doses of up to 24 units are shown in Figure 1. For doses above 24 units, use combinations of different multiple cartridges.

Figure 1. Mealtime AFREZZA Starting Dose Conversion Table

Dosage modification may be needed when:

Refer patients to the Instructions for Use for detailed instructions and visuals on how to prepare, administer, and store AFREZZA; use the AFREZZA cartridges; and use the AFREZZA inhaler. Critical administration instructions are as follows:

Inhalation Powder: single-use cartridges containing 4 units, 8 units or 12 units of insulin human as white powder to be administered via oral inhalation with the AFREZZA inhaler only [see How Supplied/Storage and Handling (16)].

{ "type": "p", "children": [], "text": "Inhalation Powder: single-use cartridges containing 4 units, 8 units or 12 units of insulin human as white powder to be administered via oral inhalation with the AFREZZA inhaler only [see How Supplied/Storage and Handling (16)].\n" }

AFREZZA is contraindicated:

{ "type": "p", "children": [], "text": "AFREZZA is contraindicated:\n" }

{ "type": "ul", "children": [ "During episodes of hypoglycemia [see Warning and Precautions (5.3)].\n", "Chronic lung disease, such as asthma or chronic obstructive pulmonary disease (COPD), because of the risk of acute bronchospasm [see Warnings and Precautions (5.1)]\n", "Hypersensitivity to regular human insulin or any of the excipients in AFREZZA [see Warnings and Precautions (5.7)]\n" ], "text": "" }

Because of the risk of acute bronchospasm, AFREZZA is contraindicated in patients with chronic lung disease such as asthma or COPD [see Contraindications (4)]. Before initiating therapy with AFREZZA, evaluate all patients with a medical history, physical examination, and spirometry (FEV1) to identify potential underlying lung disease.

Acute bronchospasm has been observed in AFREZZA-treated patients with asthma and COPD. In a study of patients with asthma whose bronchodilators were temporarily withheld for assessment, bronchoconstriction and wheezing following AFREZZA dosing was reported in 29% (5 out of 17) and 0% (0 out of 13) of patients with and without a diagnosis of asthma, respectively. In this study, a mean decline in FEV1 of 400 mL was observed 15 minutes after a single AFREZZA dose in patients with asthma. In a subset study of patients with COPD (n=8), a mean decline in FEV1 of 200 mL was observed 18 minutes after a single AFREZZA dose.

Glucose monitoring is essential for patients receiving insulin therapy. 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 under close medical supervision and the frequency of blood glucose monitoring should be increased. For patients with type 2 diabetes, dosage modifications of concomitant oral antidiabetic treatment may be needed [see Drug Interactions (7.1, 7.2, and 7.3)].

Glucose monitoring is essential for patients receiving insulin therapy. Hypoglycemia is the most common adverse reaction associated with insulins, including AFREZZA. Severe hypoglycemia can cause seizures, 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).

The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation. AFREZZA has a distinct time action profile [see Clinical Pharmacology (12)], which impacts the timing of hypoglycemia. Hypoglycemia can happen suddenly, and symptoms may differ across patients and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using certain medications [see Drug Interactions (7.4)], or in patients who experience recurrent hypoglycemia.

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 should be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

AFREZZA causes a decline in pulmonary function over time as measured by FEV1. In clinical trials excluding patients with chronic lung disease and lasting up to 2 years, AFREZZA-treated patients experienced a small [40 mL (95% CI: -80, -1)] but greater FEV1 decline than comparator-treated patients. The FEV1 decline was noted within the first 3 months, and persisted for the entire duration of therapy (up to 2 years of observation). In this population, the annual rate of FEV1 decline did not appear to worsen with increased duration of use. The effects of AFREZZA on pulmonary function for treatment duration longer than 2 years has not been established. There are insufficient data in long term studies to draw conclusions regarding reversal of the effect on FEV1 after discontinuation of AFREZZA. The observed changes in FEV1 were similar in patients with type 1 and type 2 diabetes.

Assess pulmonary function (e.g., spirometry) at baseline, after the first 6 months of therapy, and annually thereafter, even in the absence of pulmonary symptoms. In patients who have a decline of ≥ 20% in FEV1 from baseline, consider discontinuing AFREZZA. Consider more frequent monitoring of pulmonary function in patients with pulmonary symptoms such as wheezing, bronchospasm, breathing difficulties, or persistent or recurring cough. If symptoms persist, discontinue AFREZZA [see Adverse Reactions (6)].

In clinical trials, two cases of lung cancer, one in controlled trials and one in uncontrolled trials (2 cases in 2,750 patient-years of exposure), were observed in patients exposed to AFREZZA while no cases of lung cancer were observed in patients exposed to comparators (0 cases in 2,169 patient-years of exposure). In both cases, a prior history of heavy tobacco use was identified as a risk factor for lung cancer. Two additional cases of lung cancer (squamous cell and lung blastoma) occurred in non-smokers exposed to AFREZZA and were reported by investigators after clinical trial completion. These data are insufficient to determine whether AFREZZA has an effect on lung or respiratory tract tumors.

In patients with active lung cancer, a prior history of lung cancer, or in patients at risk for lung cancer, consider whether the benefits of AFREZZA use outweigh this potential risk.

In clinical trials enrolling patients with type 1 diabetes, diabetic ketoacidosis (DKA) was more common in AFREZZA-treated patients (0.43%; n=13) than in comparator-treated patients (0.14%; n=3). Patients with type 1 diabetes should always use AFREZZA in combination with basal insulin. In patients at risk for DKA, such as those with an acute illness or infection, increase the frequency of glucose monitoring and consider discontinuing AFREZZA and giving insulin using an alternate route of administration.

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including AFREZZA.

If hypersensitivity reactions occur, discontinue AFREZZA, treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6)]. AFREZZA is contraindicated in patients who have had hypersensitivity reactions to AFREZZA or any of its excipients [see Contraindications (4)].

All insulin products, including AFREZZA, 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 AFREZZA-treated patients at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations and patients receiving intravenously administered insulin).

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 AFREZZA, 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 should be considered.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure of 3,017 patients to AFREZZA and include 1,026 patients with type 1 diabetes and 1,991 patients with type 2 diabetes. The mean exposure duration was 8.2 months for patients with type 1 diabetes and those with type 2 diabetes. In the overall population:

AFREZZA was studied in placebo and active-controlled trials (n = 3 and n = 10, respectively).

The mean age of the population was 50.2 years and 20 patients were older than 75 years of age; 51% of the population were males; 83% were White, 5% were Black or African American, and 2% were Asian; 10% were Hispanic. At baseline, the type 1 diabetes population had diabetes for an average of 16.6 years and had a mean HbA1c of 8.3%, and the type 2 diabetes population had diabetes for an average of 10.7 years and had a mean HbA1c of 8.8%. At baseline, 33% of the population reported peripheral neuropathy, 32% reported retinopathy and 20% had a history of cardiovascular disease.

Table 1 shows the frequency of common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of controlled trials in type 2 diabetes patients. These adverse reactions were not present at baseline, occurred more commonly on AFREZZA than on placebo and/or comparator and occurred in at least 2% of patients treated with AFREZZA.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 1. Common Adverse Reactions That Occurred in ≥ 2% in Patients with Type 2 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA </span> </caption> <col align="left" width="33.500%"/> <col align="left" width="20.350%"/> <col align="left" width="22.225%"/> <col align="left" width="23.925%"/> <tfoot> <tr> <td align="left" colspan="4" valign="top"> <p class="First Footnote">*Carrier particle without insulin was used as placebo <span class="Italics">[see Description (<a href="#s53">11.1</a>)]</span>. </p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="middle"><span class="Bold">AFREZZA</span> <br/> <span class="Bold">(n = 1,991)</span></td><td align="center" class="Botrule Rrule" valign="middle"><span class="Bold">Placebo*</span> <br/> <span class="Bold">(n = 290)</span></td><td align="center" class="Botrule Rrule" valign="middle"><span class="Bold">Non-placebo comparators (n=1,363)</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top">Cough </td><td align="center" class="Botrule Rrule" rowspan="7" valign="middle">25.6%<br/>4.4%<br/>3.1%<br/>2.7%<br/>2.2%<br/>2.0%<br/>2.0% </td><td align="center" class="Botrule Rrule" rowspan="7" valign="middle">19.7%<br/>3.8%<br/>2.8%<br/>1.4%<br/>1.0%<br/>0.7%<br/>0.3% </td><td align="center" class="Botrule Rrule" rowspan="7" valign="middle">5.4%<br/>0.9%<br/>1.8%<br/>2.2%<br/>0.9%<br/>0.6%<br/>1.0% </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top">Throat pain or irritation </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top">Headache </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top">Diarrhea </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top">Productive cough </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top">Fatigue </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Nausea </td> </tr> </tbody> </table></div>

Table 2 shows the frequency of common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of active-controlled trials in type 1 diabetes patients. These adverse reactions were not present at baseline, occurred more commonly on AFREZZA than on comparator, and occurred in at least 2% of patients treated with AFREZZA.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 2. Common Adverse Reactions That Occurred in ≥ 2% in Patients with Type 1 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA </span> </caption> <col align="left" width="49.033%"/> <col align="left" width="25.533%"/> <col align="left" width="25.433%"/> <tbody class="Headless"> <tr> <td align="left" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">AFREZZA<br/>(n=1026)</span></td><td align="center" class="Botrule Rrule" valign="middle"><span class="Bold">Subcutaneous Insulin</span> <br/> <span class="Bold">(n = 835)</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="middle">Cough </td><td align="center" class="Rrule" valign="middle">29.4% </td><td align="center" class="Rrule" valign="middle">4.9% </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="middle">Throat pain or irritation </td><td align="center" class="Rrule" valign="middle">5.5% </td><td align="center" class="Rrule" valign="middle">1.9% </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="middle">Headache </td><td align="center" class="Rrule" valign="middle">4.7% </td><td align="center" class="Rrule" valign="middle">2.8% </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="middle">Pulmonary function test decreased </td><td align="center" class="Rrule" valign="middle">2.8% </td><td align="center" class="Rrule" valign="middle">1.0% </td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="middle">Bronchitis </td><td align="center" class="Rrule" valign="middle">2.5% </td><td align="center" class="Rrule" valign="middle">2.0% </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="middle">Urinary tract infection </td><td align="center" class="Botrule Rrule" valign="middle">2.3% </td><td align="center" class="Botrule Rrule" valign="middle">1.9% </td> </tr> </tbody> </table></div>

Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including AFREZZA [see Warnings and Precautions (5.3)]. The incidence of severe and non-severe hypoglycemia in AFREZZA-treated patients versus placebo-treated patients with type 2 diabetes is shown in Table 3. A hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with or without a blood glucose value consistent with hypoglycemia. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a blood glucose value consistent with hypoglycemia or prompt recovery after treatment for hypoglycemia.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 3. Incidence of Severe and Non-Severe Hypoglycemia in a Placebo-Controlled Study of Patients with Type 2 Diabetes </span> </caption> <col align="left" width="50.833%"/> <col align="left" width="23.733%"/> <col align="left" width="25.433%"/> <tbody class="Headless"> <tr> <td align="left" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">AFREZZA</span> <br/> <span class="Bold">(N=177)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Placebo</span> <br/> <span class="Bold">(N=176)</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" valign="top">Severe Hypoglycemia </td><td align="center" class="Rrule" valign="top">5.1% </td><td align="center" class="Rrule" valign="top">1.7% </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Non-Severe Hypoglycemia </td><td align="center" class="Botrule Rrule" valign="top">67% </td><td align="center" class="Botrule Rrule" valign="top">30% </td> </tr> </tbody> </table></div>

Cough

Approximately 27% of patients treated with AFREZZA reported cough, compared to approximately 5% of patients treated with comparator. In clinical trials, cough was the most common reason for discontinuation of AFREZZA therapy (3% of AFREZZA-treated patients).

Pulmonary Function Decline

In clinical trials lasting up to 2 years, excluding patients with chronic lung disease, patients treated with AFREZZA had a 40 mL (95% CI: -80, -1) greater decline from baseline in forced expiratory volume in one second (FEV1) compared to patients treated with comparator anti-diabetes treatments. The decline occurred during the first 3 months of therapy and persisted over 2 years (Figure 2). A decline in FEV1 of ≥ 15% occurred in 6% of AFREZZA-treated patients compared to 3% of comparator-treated patients [see Warnings and Precautions (5.4)].

Figure 2. Mean (+/-SE) Change in FEV1 (Liters) from Baseline for Type 1 and Type 2 Diabetes Patients

Weight Gain

Weight gain has occurred with some insulin therapies, including AFREZZA. Weight gain has been attributed to the anabolic effects of insulin and the decrease in glycosuria. In a clinical trial of patients with type 2 diabetes [see Clinical Studies (14.3)], there was a mean 0.49 kg weight gain among AFREZZA-treated patients compared with a mean 1.13 kg weight loss among placebo-treated patients.

The following adverse reaction has been identified during post approval use of AFREZZA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: bronchospasm.

The risk of hypoglycemia associated with AFREZZA use may be increased with antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. Dose modification and increased frequency of glucose monitoring may be required when AFREZZA is given concomitantly with these drugs.

The glucose lowering effect of AFREZZA may be decreased when given concomitantly with 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. Dose adjustment and increased frequency of glucose monitoring may be required when AFREZZA is given concomitantly with these drugs.

The glucose lowering effect of AFREZZA may be increased or decreased when co-administered with alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Dose modification and increased frequency of glucose monitoring may be required when AFREZZA is given concomitantly with these drugs.

The signs and symptoms of hypoglycemia may be blunted when beta-blockers, clonidine, guanethidine, and reserpine are given concomitantly with AFREZZA.

Risk Summary

Limited available data with AFREZZA use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes. Available information from published studies with human insulin use during pregnancy has not reported a clear association with human insulin and adverse developmental 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, there were no adverse developmental outcomes with subcutaneous administration of carrier particles (vehicle without insulin) to pregnant rats during organogenesis at doses 21 times the human daily dose of 99 mg AFREZZA, based on AUC (see Data).

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >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, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia- related morbidity.

Data

Human Data

There are limited data with AFREZZA use in pregnant women. Published data do not report a clear association with human insulin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when human insulin is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations including small sample size and lack of blinding.

Animal Data

In pregnant rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day 6 through 17 (organogenesis), no major malformations were observed at doses up to 100 mg/kg/day (21 times the human systemic exposure at a daily dose of 99 mg AFREZZA, based on AUC).

In pregnant rabbits given subcutaneous doses of 2, 10, and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day 7 through 19 (organogenesis), adverse maternal effects were observed in all dose groups (at human systemic exposure following a daily dose of 99 mg AFREZZA, based on AUC).

In pregnant rats given subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier particles (vehicle without insulin) from gestation day 7 through lactation day 20 (weaning), decreased epididymis and testes weights were observed in F1 male offspring, however, no decrease in fertility was noted, and impaired learning were observed in F1 pups at ³ 30 mg/kg/day (6 times the human systemic exposure at a daily dose of 99 mg AFREZZA, based on AUC).

Risk Summary

There are no data on the presence of AFREZZA in human milk, the effects on the breastfed infant, or the effects on milk production. One small published study reported that exogenous subcutaneous insulin was present in human milk. No adverse effects in infants were noted. The carrier particles are present in rat milk (see Data). Potential adverse reactions that are related to inhalational administration of AFREZZA are unlikely to be associated with potential exposure of AFREZZA through breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for AFREZZA and any potential adverse effects on the breastfed infant from AFREZZA or from the underlying maternal condition.

Data

Subcutaneous administration of the carrier particle in lactating rats resulted in excretion of the carrier particle in rat milk at levels that were approximately 10% of the maternal exposure. Given the results of the rat study, it is highly likely that the insulin and carrier in AFREZZA are excreted in human milk.

The safety and effectiveness of AFREZZA to improve glycemic control in pediatric patients with diabetes mellitus has not been established. AFREZZA has not been studied in pediatric patients.

In the AFREZZA clinical studies, 671 (12%) patients were 65 years of age or older, of which 42 (0.8%) were 75 years of age or older. In these studies, 381 (13%) of AFREZZA-treated patients were 65 years of age or older, of which 20 (0.7%) were 75 years of age or older. No overall differences in effectiveness of AFREZZA have been observed between patients 65 years of age and older and younger adult patients [see Clinical Studies (14)]. Clinical studies of AFREZZA did not include sufficient numbers of patients 65 years of age and older to determine whether there were differences in safety between these patients and younger adult patients.

Pharmacokinetic and pharmacodynamic studies to assess the effect of age on pharmacokinetics or pharmacodynamics on insulin human, respectively, have not been conducted.

The effect of hepatic impairment on the pharmacokinetics of AFREZZA has not been studied. Frequent glucose monitoring and a lower dosage may be necessary in AFREZZA-treated patients with hepatic impairment [see Warnings and Precautions (5.3)].

The effect of renal impairment on the pharmacokinetics of AFREZZA has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. Frequent glucose monitoring and a lower dosage may be necessary in AFREZZA-treated patients with renal impairment [see Warnings and Precautions (5.3)].

Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.8)].

{ "type": "p", "children": [], "text": "Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.8)].\n" }

Mild episodes of hypoglycemia due to insulin overdose can usually be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed.

{ "type": "p", "children": [], "text": "Mild episodes of hypoglycemia due to insulin overdose can usually be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed.\n" }

Severe episodes of hypoglycemia (due to insulin overdose) with coma, seizure, or neurologic impairment may be treated with intramuscular or subcutaneous glucagon or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycemia. Hypokalemia should be corrected appropriately.

{ "type": "p", "children": [], "text": "Severe episodes of hypoglycemia (due to insulin overdose) with coma, seizure, or neurologic impairment may be treated with intramuscular or subcutaneous glucagon or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycemia. Hypokalemia should be corrected appropriately.\n" }

Human insulin is a rapid acting human insulin produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12). Chemically, human insulin has the empirical formula C257H383N65O77S6 and a molecular weight of 5808. Human insulin has the following primary amino acid sequence:

AFREZZA (human insulin) inhalation powder is available in single-use plastic cartridges filled with a white powder containing insulin (human), which is administered via oral inhalation using the AFREZZA Inhaler only.

Insulin is adsorbed onto carrier particles consisting of fumaryl diketopiperazine (FDKP) and polysorbate 80.

AFREZZA Inhalation Powder is a dry powder supplied as 4 unit, 8 unit or 12 unit cartridges.

The AFREZZA Inhaler is breath-powered by the patient. When the patient inhales through the device, the powder is aerosolized and delivered to the lung. The amount of AFREZZA delivered to the lung will depend on individual patient factors.

Insulin lowers blood glucose levels in adult patients with diabetes mellitus by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in adipocytes, inhibits proteolysis, and enhances protein synthesis.

The time course of insulin action (i.e., glucose lowering) may vary considerably in different patients or within the same patient. The average pharmacodynamic profile [i.e., glucose lowering effect measured by glucose infusion rate (GIR) over time in a euglycemic clamp study] after administration of a single AFREZZA dose of 4, 12, and 48 units in 30 patients with type 1 diabetes is shown in Figure 3(A), and key characteristics regarding the timing of the effects are described in Table 4:

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 4. Timing of Insulin Effect (i.e., mean pharmacodynamics effect) After Administration of a Single AFREZZA Dose in Patients (N=30) with Type 1 Diabetes Mellitus </span> </caption> <col align="left" width="35.000%"/> <col align="left" width="21.675%"/> <col align="left" width="20.825%"/> <col align="left" width="22.500%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Parameter for Insulin Effect</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">AFREZZA 4 units</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">AFREZZA 12 units</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">AFREZZA 48 units</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Time to first measurable effect </td><td align="center" class="Botrule Rrule" valign="top">~12 minutes </td><td align="center" class="Botrule Rrule" valign="top">~12 minutes </td><td align="center" class="Botrule Rrule" valign="top">~12 minutes </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Time to peak effect </td><td align="center" class="Botrule Rrule" valign="top">~35 minutes </td><td align="center" class="Botrule Rrule" valign="top">~45 minutes </td><td align="center" class="Botrule Rrule" valign="top">~55 minutes </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Time for effect to return to baseline </td><td align="center" class="Botrule Rrule" valign="top">~90 minutes </td><td align="center" class="Botrule Rrule" valign="top">~180 minutes </td><td align="center" class="Botrule Rrule" valign="top">~270 minutes </td> </tr> </tbody> </table></div>

Figure 3. Results After Administration of AFREZZA 4, 12, and 48 Units in Patients with T1DM (N=30) A) Mean Insulin Effect (Baseline-Corrected Glucose Infusion Rate); and B) Pharmacokinetic (Baseline-Corrected Serum Insulin Concentration Profiles)

On average, the pharmacodynamics effect of AFREZZA, measured as area under the glucose infusion rate – time curve (AUC GIR) increased linearly with doses up to 48 units (106, 387, and 1581 mg/kg for 4, 12, and 48 units doses, respectively).

Intrapatient variability in AUC GIR and GIRmax was approximately 28% (95% CI 21-42%) and 27% (95% CI 20-40%), respectively.

The area under the plasma concentration versus time curve (AUC) of insulin increased dose proportionally up to 48 units. Intrapatient variability of AUC and peak concentration (Cmax) of insulin was approximately 16% (95% CI 12-23%) and 21% (95% CI 16-30%), respectively.

Absorption

The pharmacokinetic profiles for orally inhaled AFREZZA 4, 12, and 48 units from a study in 30 patients with type 1 diabetes are shown in Figure 5(B). The time to maximum serum insulin concentration (tmax) ranged from 10-20 minutes after oral inhalation of 4 to 48 units of AFREZZA.

Elimination

The apparent terminal half-life ranged from 120 to 206 minutes. Serum insulin concentrations declined to baseline by approximately 60 to 240 minutes.

Metabolism and Excretion

The metabolism and excretion of AFREZZA are comparable to regular human insulin.

Carrier Particles

Clinical pharmacology studies showed that carrier particles [see Description (11.1)] are not metabolized and are eliminated unchanged in the urine following the lung absorption. Following oral inhalation of AFREZZA, a mean of 39% of the inhaled dose of carrier particles was distributed to the lungs and a mean of 7% of the dose was swallowed. The swallowed fraction was not absorbed from the GI tract and was eliminated unchanged in the feces.

Drug Interaction Studies

Bronchodilators and Inhaled Steroids

Albuterol increased the AUC insulin after AFREZZA administration by 25% in patients with asthma [see Drug Interactions (7.2)]. AFREZZA is contraindicated in patients with asthma.

In a study in healthy volunteers no significant change in insulin exposure was observed when fluticasone was administered following AFREZZA administration.

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of insulin human or of other insulin human products.

Increases in anti-insulin antibody concentrations were observed in patients treated with AFREZZA. Increases in anti-insulin antibodies were observed more frequently in patients treated with AFREZZA than in patients treated with subcutaneously injected mealtime insulin. There was no clinically significant effect of anti-drug antibodies on safety or effectiveness (as measured by HbA1c and fasting plasma glucose) of AFREZZA over the treatment duration of the studies which spanned 3 to 24 months.

In a 104 week carcinogenicity study, rats were given doses up to 46 mg/kg/day of the carrier and up to 1.23 mg/kg/day of insulin, by nose-only inhalation. No increased incidence of tumors was observed at systemic exposures equivalent to the insulin at a daily AFREZZA dose of 99 mg, based on a comparison of relative body surface areas across species.

No increased incidence of tumors was observed in a 26 week carcinogenicity study in transgenic mice (Tg-ras-H2) given doses up to 75 mg/kg/day of carrier and up to 5 mg/kg/day of AFREZZA.

AFREZZA was not genotoxic in Ames bacterial mutagenicity assay and in the chromosome aberration assay, using human peripheral lymphocytes with or without metabolic activation. The carrier alone was not genotoxic in the in vivo mouse micronucleus assay.

In fertility study in male and female rats at subcutaneous doses of 10, 30, and 100 mg/kg/day of carrier (vehicle without insulin), there were no adverse effects on male fertility at doses up to 100 mg/kg/day. In female rats dosed 2 weeks prior to mating until gestation day 7, there was increased pre- and post-implantation loss at 100 mg/kg/day but not at 30 mg/kg/day (21 times and 6 times, respectively the human systemic exposure at a daily dose of 99 mg AFREZZA, based on AUC).

AFREZZA has been studied in adults with type 1 diabetes in combination with basal insulin. The efficacy of AFREZZA, in combination with basal insulin, in type 1 diabetes patients was compared to insulin aspart in combination with basal insulin.

AFREZZA has been studied in adults with type 2 diabetes in combination with oral antidiabetic drugs. The efficacy of AFREZZA in type 2 diabetes patients was compared to placebo inhalation.

Patients with inadequately controlled type 1 diabetes participated in a 24-week, open-label, active-controlled study to evaluate the glucose lowering effect of mealtime AFREZZA used in combination with a basal insulin. Following a 4-week basal insulin optimization period, 344 patients were randomized to AFREZZA by oral inhalation (n=174) or insulin aspart given subcutaneously (n=170) at each meal of the day. All patients received basal insulin. Mealtime insulin doses were titrated to glycemic goals for the first 12 weeks and kept stable for the last 12 weeks of the study.

Results

At Week 24, treatment with mealtime AFREZZA and basal insulin provided a mean reduction in HbA1c that met the pre-specified non-inferiority margin of 0.4%. AFREZZA and basal insulin provided less HbA1c reduction than insulin aspart and basal insulin, and the difference was statistically significant. More patients in the insulin aspart and basal insulin group achieved the HbA1c target of ≤7% (Table 5).

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 5. Results at Week 24 in an Active-Controlled Study of Mealtime AFREZZA plus Basal Insulin in Adults with Type 1 Diabetes </span> </caption> <col align="left" width="55.467%"/> <col align="left" width="22.267%"/> <col align="left" width="22.267%"/> <tfoot> <tr class="First"> <td align="left" class="Lrule Rrule" colspan="3" valign="top"> <p class="First Footnote"> <span class="Sup">a</span> Adjusted mean was obtained using a Mixed Model Repeated Measures (MMRM) approach with HbA1c or FPG as the dependent variable and treatment, visit, region, basal insulin stratum, and treatment by visit interaction as fixed factors, and corresponding baseline as a covariate. An autoregression (1) [AR(1)] covariance structure was used. </p> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="3" valign="top"> <p class="First Footnote"> <span class="Sup">b</span> Data at 24 weeks were available from 131 (75%) and 150 (88%) patients randomized to the AFREZZA and insulin aspart groups, respectively. </p> </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First Footnote"> <span class="Sup">c</span> The percentage was calculated based on the number of patients randomized to the trial. </p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Efficacy Parameter</span></td><td align="center" class="Botrule Rrule Toprule" valign="middle"><span class="Bold">AFREZZA + Basal Insulin (N=174)</span></td><td align="center" class="Botrule Rrule Toprule" valign="middle"><span class="Bold">Insulin Aspart + Basal Insulin<br/>(N=170)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">HbA1c (%) </td><td align="left" class="Botrule Rrule" valign="top"></td><td align="left" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Baseline (adjusted mean<span class="Sup">a</span>) </td><td align="center" class="Botrule Rrule" valign="top">7.94 </td><td align="center" class="Botrule Rrule" valign="top">7.92 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Change from baseline (adjusted mean<span class="Sup">a,b</span>) </td><td align="center" class="Botrule Rrule" valign="top">-0.21 </td><td align="center" class="Botrule Rrule" valign="top">-0.40 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Difference from insulin aspart (adjusted mean<span class="Sup">a,b</span>)<br/>      (95% CI) </td><td align="center" class="Botrule Rrule" colspan="2" valign="top">0.19<br/>(0.02, 0.36) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Percentage of patients achieving HbA1c ≤ 7%<span class="Sup">c</span></td><td align="center" class="Botrule Rrule" valign="top">14% </td><td align="center" class="Botrule Rrule" valign="top">27% </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="3" valign="top">      </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Fasting Plasma Glucose (mg/dL) </td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Baseline (adjusted mean<span class="Sup">a</span>) </td><td align="center" class="Botrule Rrule" valign="top">153.9 </td><td align="center" class="Botrule Rrule" valign="top">151.6 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Change from baseline (adjusted mean<span class="Sup">a, b</span>) </td><td align="center" class="Botrule Rrule" valign="top">-25.3 </td><td align="center" class="Botrule Rrule" valign="top">10.2 </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="middle">     Difference from insulin aspart (adjusted mean<span class="Sup">a, b</span>)<br/>      (95% CI) </td><td align="center" class="Botrule Rrule" colspan="2" valign="middle">-35.4<br/>(-56.3, -14.6) </td> </tr> </tbody> </table></div>

A total of 479 adult patients with type 2 diabetes inadequately controlled on optimal/maximally tolerated doses of metformin only, or 2 or more oral antidiabetic (OAD) agents participated in a 24-week, double-blind, placebo-controlled study. Following a 6-week run-in period, 353 patients were randomized to AFREZZA by oral inhalation (n=177) or an inhaled placebo powder without insulin (n=176). Insulin doses were titrated for the first 12 weeks and kept stable for the last 12 weeks of the study. OADs doses were kept stable in the study.

Results

At Week 24, treatment with AFREZZA plus OADs provided a mean reduction in HbA1c that was statistically significantly greater compared to the HbA1c reduction observed in the placebo plus OADs group (Table 6).

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 6. Results at Week 24 in a Placebo-Controlled Study of AFREZZA in Adults with Type 2 Diabetes Inadequately Controlled on Oral Antidiabetic Agents </span> </caption> <col align="left" width="48.800%"/> <col align="left" width="25.633%"/> <col align="left" width="25.567%"/> <tfoot> <tr class="First"> <td align="left" class="Lrule Rrule" colspan="3" valign="top"> <p class="First Footnote"> <span class="Sup">a</span> Adjusted mean was obtained using a Mixed Model Repeated Measures (MMRM) approach with HbA1c or FPG as the dependent variable and treatment, visit, region, and treatment by visit interaction as fixed factors, and corresponding baseline as a covariate. An autoregression (1) [AR(1)] covariance structure was used. </p> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="3" valign="top"> <p class="First Footnote"> <span class="Sup">b</span> Data at 24 weeks without rescue therapy were available from 139 (79%) and 129 (73%) patients randomized to the AFREZZA and placebo groups, respectively. </p> </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top"> <p class="First Footnote"> <span class="Sup">c</span> The percentage was calculated based on the number of patients randomized to the trial. </p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="middle"><span class="Bold">Efficacy Parameter</span></td><td align="center" class="Botrule Rrule Toprule" valign="middle"><span class="Bold">AFREZZA + Oral Anti-Diabetic Agents<br/>(N=177)</span></td><td align="center" class="Botrule Rrule Toprule" valign="middle"><span class="Bold">Placebo + Oral Anti-Diabetic Agents<br/>(N=176)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">HbA1c (%) </td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Baseline (adjusted mean<span class="Sup">a</span>) </td><td align="center" class="Botrule Rrule" valign="top">8.25 </td><td align="center" class="Botrule Rrule" valign="top">8.27 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Change from baseline (adjusted mean<span class="Sup">a,b</span>) </td><td align="center" class="Botrule Rrule" valign="top">-0.82 </td><td align="center" class="Botrule Rrule" valign="top">-0.42 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Difference from placebo (adjusted mean<span class="Sup">a,b</span>)<br/>      (95% CI) </td><td align="center" class="Botrule Rrule" colspan="2" valign="top">-0.40<br/>(-0.57, -0.23) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Percentage (%) of patients achieving HbA1C ≤7%<span class="Sup">c</span></td><td align="center" class="Botrule Rrule" valign="top">32% </td><td align="center" class="Botrule Rrule" valign="top">15% </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="3" valign="top">  </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Fasting Plasma Glucose (mg/dL) </td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Baseline (adjusted mean<span class="Sup">a</span>) </td><td align="center" class="Botrule Rrule" valign="top">175.9 </td><td align="center" class="Botrule Rrule" valign="top">175.2 </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Change from baseline (adjusted mean<span class="Sup">a,b</span>) </td><td align="center" class="Botrule Rrule" valign="top">-11.2 </td><td align="center" class="Botrule Rrule" valign="top">-3.8 </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">     Difference from placebo (adjusted mean<span class="Sup">a,b</span>)<br/>      (95% CI) </td><td align="center" class="Botrule Rrule" colspan="2" valign="top">-7.4<br/>(-18.0, 3.2) </td> </tr> </tbody> </table></div>

Storage:

Not in Use: Refrigerated Storage 2-8ºC (36-46ºF)

<div class="scrollingtable"><table width="100%"> <col align="left" width="50.000%"/> <col align="left" width="50.000%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="2" valign="top"> <p class="First Footnote">* If a foil package, blister card or strip is not refrigerated, the contents must be used within 10 days. </p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Sealed (Unopened) Foil Package </td><td align="left" class="Botrule Rrule Toprule" valign="top">May be stored until the Expiration Date* </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Sealed (Unopened) Blister Cards + Strips </td><td align="left" class="Botrule Rrule" valign="top">Must be used within 1 month* </td> </tr> </tbody> </table></div>

In Use: Room Temperature Storage 25ºC (77ºF), excursions permitted 15-30ºC (59-86ºF)

<div class="scrollingtable"><table width="100%"> <col align="left" width="50.000%"/> <col align="left" width="50.000%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top">Sealed (Unopened) Blister Cards + Strips </td><td align="left" class="Botrule Rrule Toprule" valign="top">Must be used within 10 days </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Opened Strips </td><td align="left" class="Botrule Rrule" valign="top">Must be used within 3 days </td> </tr> </tbody> </table></div>

Do not put a blister card or strip back into the refrigerator after being stored at room temperature.

Inhaler Storage:

Store refrigerated or at room temperature 2-25ºC (36-77ºF); excursions permitted. Inhaler may be stored refrigerated, but should be at room temperature before use.

Handling:

Before use, cartridges should be at room temperature for 10 minutes.

Common Adverse Reactions

Inform patients that the most common adverse reactions associated with the use of AFREZZA are hypoglycemia, cough, and throat pain or irritation.

Pregnancy

Advise women with diabetes to inform their physician if they are pregnant or are planning to become pregnant while using AFREZZA.

Acute Bronchospasm in Patients with Chronic Lung Disease

Advise patients that if they experience any respiratory difficulty after inhalation of AFREZZA, they should report it to their healthcare provider immediately for assessment.

Hypoglycemia

Instruct patients on self-management procedures including glucose monitoring, proper inhalation technique, and management of hypoglycemia and hyperglycemia especially at initiation of AFREZZA 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, or skipped meals.

Instruct patients on the management of hypoglycemia. 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 [see Warnings and Precautions (5.3)].

Decline in Pulmonary Function

Inform patients that AFREZZA can cause a decline in lung function [see Warnings and Precautions (5.4)].

Lung Cancer

Inform patients to promptly report any signs or symptoms potentially related to lung cancer [see Warnings and Precautions (5.5)].

Diabetic Ketoacidosis

Instruct patients to carefully monitor their blood glucose during illness, infection, and other risk situations for diabetic ketoacidosis and to contact their healthcare provider if their blood glucose control worsens [see Warnings and Precautions (5.6)].

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions can occur with insulin therapy including AFREZZA. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.7)].

Manufactured by: MannKind Corporation, Danbury, CT 06810US License No. #2190© 2016 – 2023 MannKind Corporation

AFREZZA is a registered trademark of MannKind CorporationPatent: www.mannkindcorp.com/patent-notices

<div class="scrollingtable"><table width="100%"> <col align="left" width="80.250%"/> <col align="left" width="19.750%"/> <tfoot> <tr class="First Last"> <td align="left" valign="top"> <p class="First Footnote">This Medication Guide has been approved by the U.S. Food and Drug Administration </p> </td><td align="right" valign="top"> <p class="First Footnote">Revised 02/2023 </p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">MEDICATION GUIDE</span> <br/> <span class="Bold">AFREZZA® (uh-FREZZ-uh)</span> <br/> <span class="Bold">(insulin human)</span> <br/> <span class="Bold">inhalation powder, for oral inhalation use</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <a name="p01"></a><span class="Bold">What is the most important information I should know about AFREZZA?</span> <br/> <span class="Bold">AFREZZA can cause serious side effects, including:</span> <br/> </p> <ul class="Disc"> <li> <span class="Bold">Sudden lung problems (bronchospasms). Do not use AFREZZA if you have long-term (chronic) lung problems such as asthma or chronic obstructive pulmonary disease (COPD).</span> Before starting AFREZZA, your healthcare provider will give you a breathing test to check how your lungs are working. </li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">What is AFREZZA?</span> <br/> <ul class="Disc"> <li>AFREZZA is a man-made insulin that is breathed-in through your lungs (inhaled) and is used to control high blood sugar in adults with diabetes mellitus. </li> <li>AFREZZA is not for use to treat diabetic ketoacidosis. AFREZZA must be used with basal insulin in people who have type 1 diabetes mellitus. </li> <li>It is not known if AFREZZA is safe and effective for use in people who smoke. AFREZZA is not for use in people who smoke or have recently stopped smoking (less than 6 months). </li> <li>It is not known if AFREZZA is safe and effective in children under 18 years of age. </li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Who should not use AFREZZA?</span> <br/> <span class="Bold">Do not use AFREZZA if you:</span> <br/> <ul class="Disc"> <li>Have chronic lung problems such as asthma or COPD. </li> <li>Are allergic to regular human insulin or any of the ingredients in AFREZZA. See the end of this Medication Guide for a complete list of ingredients in AFREZZA. </li> <li> <span class="Bold">Are having an episode of low blood sugar (hypoglycemia).</span> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">What should I tell my healthcare provider before using AFREZZA?</span> <br/> <span class="Bold">Before using AFREZZA, tell your healthcare provider about all your medical conditions, including if you:</span> <br/> <ul class="Disc"> <li>Have lung problems such as asthma or COPD </li> <li>Have or have had lung cancer </li> <li>Are using any inhaled medications </li> <li>Smoke or have recently stopped smoking </li> <li>Have kidney or liver problems </li> <li>Are pregnant, planning to become pregnant, or are breastfeeding. AFREZZA may harm your unborn or breastfeeding baby. </li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top">Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins or herbal supplements.<br/> <span class="Bold">Before you start using AFREZZA, talk to your healthcare provider about low blood sugar and how to manage it.</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">How should I use AFREZZA?</span> <br/> <ul class="Disc"> <li>Read the detailed <span class="Bold"><a href="#s88">Instructions for Use</a></span> that comes with your AFREZZA. </li> <li>Take AFREZZA exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much AFREZZA to use and when to use it. </li> <li>Know the strength of AFREZZA you use. <span class="Bold">Do not</span> change the amount of AFREZZA you use unless your healthcare provider tells you to. </li> <li>Take AFREZZA at the beginning of your meal. </li> <li> <span class="Bold">Check your blood sugar levels.</span> Ask your healthcare provider what your blood sugar should be and when you should check your blood sugar levels. </li> <li> <span class="Bold">Keep AFREZZA and all medicines out of the reach of children.</span> </li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Your dose of AFREZZA may need to change because of:</span> <br/> <ul class="Disc"> <li>Change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take. </li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">What should I avoid while using AFREZZA?</span> <br/> <span class="Bold">While using AFREZZA do not:</span> <br/> <ul class="Disc"> <li>Drive or operate heavy machinery, until you know how AFREZZA affects you </li> <li>Drink alcohol or use over-the-counter medicines that contain alcohol </li> <li>Smoke </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">What are the possible side effects of AFREZZA?</span> <br/> <ul class="Disc"> <li> <span class="Bold">AFREZZA may cause serious side effects that can lead to death, including:</span> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">See “<a href="#p01">What is the most important information I should know about AFREZZA?</a>”</span> <br/> <ul class="Disc"> <li> <span class="Bold">Low blood sugar (hypoglycemia).</span> Signs and symptoms that may indicate low blood sugar include:<ul class="Circle"> <li>Dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood change, hunger. </li> </ul> </li> <li> <span class="Bold">Decreased lung function.</span> Your healthcare provider should check how your lungs are working before you start using AFREZZA, 6 months after you start using it and yearly after that. </li> <li> <span class="Bold">Lung cancer.</span> In studies of AFREZZA in people with diabetes, lung cancer occurred in a few more people who were taking AFREZZA than in people who were taking other diabetes medications. There were too few cases to know if lung cancer was related to AFREZZA. If you have lung cancer, you and your healthcare provider should decide if you should use AFREZZA. </li> <li> <span class="Bold">Diabetic ketoacidosis.</span> Talk to your healthcare provider if you have an illness. Your AFREZZA dose or how often you check your blood sugar may need to be changed. </li> <li> <span class="Bold">Severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or symptoms of a severe allergic reaction:</span> <ul class="Circle"> <li>A rash over your whole body, trouble breathing, a fast heartbeat, or sweating. </li> </ul> </li> <li> <span class="Bold">Low potassium in your blood (hypokalemia).</span> </li> <li> <span class="Bold">Heart failure.</span> Taking certain diabetes pills called thiazolidinediones or “TZDs” with AFREZZA may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with AFREZZA. Your healthcare provider should monitor you closely while you are taking TZDs with AFREZZA. Tell your healthcare provider if you have any new or worse symptoms of heart failure including:<ul class="Circle"> <li>Shortness of breath, swelling of your ankles or feet, sudden weight gain. </li> </ul> <p class="First">Treatment with TZDs and AFREZZA may need to be changed or stopped by your healthcare provider if you have new or worse heart failure. </p> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">Get emergency medical help if you have:</span> <br/> <ul class="Disc"> <li>Trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion. </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="2" valign="top"><span class="Bold">The most common side effects of AFREZZA include:</span> <br/> <ul class="Disc"> <li>Low blood sugar (hypoglycemia), cough, sore throat. </li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">These are not all the possible side effects of AFREZZA.</span> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 (1-800-332-1088). </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">General information about the safe and effective use of AFREZZA.</span> <br/>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use AFREZZA for a condition for which it was not prescribed. Do not give AFREZZA to other people, even if they have the same symptoms that you have. It may harm them.<br/>This Medication Guide summarizes the most important information about AFREZZA. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about AFREZZA that is written for health professionals. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">What are the ingredients in AFREZZA?</span> <br/> <span class="Bold">Active ingredient:</span> human insulin<br/> <span class="Bold">Inactive ingredients:</span> fumaryl diketopiperazine, polysorbate 80 </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top">AFREZZA is a registered trademark of MannKind Corporation<br/>Patent: www.mannkindcorp.com/patent-notices<br/>Manufactured by: MannKind Corporation, Danbury, CT 06810<br/>US License No. #2190<br/>© 2016 – 2023 MannKind Corporation<br/>For more information, go to www.AFREZZA.com or call MannKind Corporation at 1-877-323-8505. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" width=\"80.250%\"/>\n<col align=\"left\" width=\"19.750%\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" valign=\"top\">\n<p class=\"First Footnote\">This Medication Guide has been approved by the U.S. Food and Drug Administration\n</p>\n</td><td align=\"right\" valign=\"top\">\n<p class=\"First Footnote\">Revised 02/2023\n</p>\n</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">MEDICATION GUIDE</span>\n<br/>\n<span class=\"Bold\">AFREZZA® (uh-FREZZ-uh)</span>\n<br/>\n<span class=\"Bold\">(insulin human)</span>\n<br/>\n<span class=\"Bold\">inhalation powder, for oral inhalation use</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<a name=\"p01\"></a><span class=\"Bold\">What is the most important information I should know about AFREZZA?</span>\n<br/>\n<span class=\"Bold\">AFREZZA can cause serious side effects, including:</span>\n<br/>\n</p>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Sudden lung problems (bronchospasms). Do not use AFREZZA if you have long-term (chronic) lung problems such as asthma or chronic obstructive pulmonary disease (COPD).</span> Before starting AFREZZA, your healthcare provider will give you a breathing test to check how your lungs are working.\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">What is AFREZZA?</span>\n<br/>\n<ul class=\"Disc\">\n<li>AFREZZA is a man-made insulin that is breathed-in through your lungs (inhaled) and is used to control high blood sugar in adults with diabetes mellitus.\n</li>\n<li>AFREZZA is not for use to treat diabetic ketoacidosis. AFREZZA must be used with basal insulin in people who have type 1 diabetes mellitus.\n</li>\n<li>It is not known if AFREZZA is safe and effective for use in people who smoke. AFREZZA is not for use in people who smoke or have recently stopped smoking (less than 6 months).\n</li>\n<li>It is not known if AFREZZA is safe and effective in children under 18 years of age.\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Who should not use AFREZZA?</span>\n<br/>\n<span class=\"Bold\">Do not use AFREZZA if you:</span>\n<br/>\n<ul class=\"Disc\">\n<li>Have chronic lung problems such as asthma or COPD.\n</li>\n<li>Are allergic to regular human insulin or any of the ingredients in AFREZZA. See the end of this Medication Guide for a complete list of ingredients in AFREZZA.\n</li>\n<li>\n<span class=\"Bold\">Are having an episode of low blood sugar (hypoglycemia).</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">What should I tell my healthcare provider before using AFREZZA?</span>\n<br/>\n<span class=\"Bold\">Before using AFREZZA, tell your healthcare provider about all your medical conditions, including if you:</span>\n<br/>\n<ul class=\"Disc\">\n<li>Have lung problems such as asthma or COPD\n</li>\n<li>Have or have had lung cancer\n</li>\n<li>Are using any inhaled medications\n</li>\n<li>Smoke or have recently stopped smoking\n</li>\n<li>Have kidney or liver problems\n</li>\n<li>Are pregnant, planning to become pregnant, or are breastfeeding. AFREZZA may harm your unborn or breastfeeding baby.\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins or herbal supplements.<br/>\n<span class=\"Bold\">Before you start using AFREZZA, talk to your healthcare provider about low blood sugar and how to manage it.</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">How should I use AFREZZA?</span>\n<br/>\n<ul class=\"Disc\">\n<li>Read the detailed <span class=\"Bold\"><a href=\"#s88\">Instructions for Use</a></span> that comes with your AFREZZA.\n</li>\n<li>Take AFREZZA exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much AFREZZA to use and when to use it.\n</li>\n<li>Know the strength of AFREZZA you use. <span class=\"Bold\">Do not</span> change the amount of AFREZZA you use unless your healthcare provider tells you to.\n</li>\n<li>Take AFREZZA at the beginning of your meal.\n</li>\n<li>\n<span class=\"Bold\">Check your blood sugar levels.</span> Ask your healthcare provider what your blood sugar should be and when you should check your blood sugar levels.\n</li>\n<li>\n<span class=\"Bold\">Keep AFREZZA and all medicines out of the reach of children.</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Your dose of AFREZZA may need to change because of:</span>\n<br/>\n<ul class=\"Disc\">\n<li>Change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take.\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">What should I avoid while using AFREZZA?</span>\n<br/>\n<span class=\"Bold\">While using AFREZZA do not:</span>\n<br/>\n<ul class=\"Disc\">\n<li>Drive or operate heavy machinery, until you know how AFREZZA affects you\n</li>\n<li>Drink alcohol or use over-the-counter medicines that contain alcohol\n</li>\n<li>Smoke\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">What are the possible side effects of AFREZZA?</span>\n<br/>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">AFREZZA may cause serious side effects that can lead to death, including:</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">See “<a href=\"#p01\">What is the most important information I should know about AFREZZA?</a>”</span>\n<br/>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Low blood sugar (hypoglycemia).</span> Signs and symptoms that may indicate low blood sugar include:<ul class=\"Circle\">\n<li>Dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood change, hunger.\n</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">Decreased lung function.</span> Your healthcare provider should check how your lungs are working before you start using AFREZZA, 6 months after you start using it and yearly after that.\n</li>\n<li>\n<span class=\"Bold\">Lung cancer.</span> In studies of AFREZZA in people with diabetes, lung cancer occurred in a few more people who were taking AFREZZA than in people who were taking other diabetes medications. There were too few cases to know if lung cancer was related to AFREZZA. If you have lung cancer, you and your healthcare provider should decide if you should use AFREZZA.\n</li>\n<li>\n<span class=\"Bold\">Diabetic ketoacidosis.</span> Talk to your healthcare provider if you have an illness. Your AFREZZA dose or how often you check your blood sugar may need to be changed.\n</li>\n<li>\n<span class=\"Bold\">Severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or symptoms of a severe allergic reaction:</span>\n<ul class=\"Circle\">\n<li>A rash over your whole body, trouble breathing, a fast heartbeat, or sweating.\n</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">Low potassium in your blood (hypokalemia).</span>\n</li>\n<li>\n<span class=\"Bold\">Heart failure.</span> Taking certain diabetes pills called thiazolidinediones or “TZDs” with AFREZZA may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with AFREZZA. Your healthcare provider should monitor you closely while you are taking TZDs with AFREZZA. Tell your healthcare provider if you have any new or worse symptoms of heart failure including:<ul class=\"Circle\">\n<li>Shortness of breath, swelling of your ankles or feet, sudden weight gain.\n</li>\n</ul>\n<p class=\"First\">Treatment with TZDs and AFREZZA may need to be changed or stopped by your healthcare provider if you have new or worse heart failure.\n</p>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Get emergency medical help if you have:</span>\n<br/>\n<ul class=\"Disc\">\n<li>Trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion.\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">The most common side effects of AFREZZA include:</span>\n<br/>\n<ul class=\"Disc\">\n<li>Low blood sugar (hypoglycemia), cough, sore throat.\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">These are not all the possible side effects of AFREZZA.</span> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 (1-800-332-1088).\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">General information about the safe and effective use of AFREZZA.</span>\n<br/>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use AFREZZA for a condition for which it was not prescribed. Do not give AFREZZA to other people, even if they have the same symptoms that you have. It may harm them.<br/>This Medication Guide summarizes the most important information about AFREZZA. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about AFREZZA that is written for health professionals.\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">What are the ingredients in AFREZZA?</span>\n<br/>\n<span class=\"Bold\">Active ingredient:</span> human insulin<br/>\n<span class=\"Bold\">Inactive ingredients:</span> fumaryl diketopiperazine, polysorbate 80\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">AFREZZA is a registered trademark of MannKind Corporation<br/>Patent: www.mannkindcorp.com/patent-notices<br/>Manufactured by: MannKind Corporation, Danbury, CT 06810<br/>US License No. #2190<br/>© 2016 – 2023 MannKind Corporation<br/>For more information, go to www.AFREZZA.com or call MannKind Corporation at 1-877-323-8505.\n</td>\n</tr>\n</tbody>\n</table></div>" }

INSTRUCTIONS FOR USEAFREZZA® (uh-FREZZ-uh)(insulin human) inhalation powder, for oral inhalation use

{ "type": "p", "children": [], "text": "\nINSTRUCTIONS FOR USEAFREZZA® (uh-FREZZ-uh)(insulin human) inhalation powder, for oral inhalation use\n" }

This “Instructions for Use” contains information on how to use AFREZZA® (insulin human) Inhalation Powder.

{ "type": "p", "children": [], "text": "This “Instructions for Use” contains information on how to use AFREZZA® (insulin human) Inhalation Powder.\n" }

Read this Instructions for Use before you start using AFREZZA and each time you get a new AFREZZA Inhaler. 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.

{ "type": "p", "children": [], "text": "Read this Instructions for Use before you start using AFREZZA and each time you get a new AFREZZA Inhaler. 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.\n" }

Your healthcare provider should show you how to use your AFREZZA Inhaler the right way before you use it for the first time.

{ "type": "p", "children": [], "text": "\nYour healthcare provider should show you how to use your AFREZZA Inhaler the right way before you use it for the first time.\n" }

Important information about AFREZZA:

{ "type": "p", "children": [], "text": "\nImportant information about AFREZZA:\n" }

{ "type": "ul", "children": [ "\nAFREZZA comes in 3 strengths (see Figure A):\n4 units (blue cartridge)\n\n8 units (green cartridge)\n\n12 units (yellow cartridge)\n\n\n" ], "text": "" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" width="100.000%"/> <tbody class="Headless"> <tr> <td align="center" valign="top"><a name="f05"></a><img alt="Figure A " src="/dailymed/image.cfm?name=afr01-0006-05.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td> </tr> <tr> <td align="center" valign="top"><span class="Bold">Figure A</span></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col align=\"left\" width=\"100.000%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"center\" valign=\"top\"><a name=\"f05\"></a><img alt=\"Figure A\n\" src=\"/dailymed/image.cfm?name=afr01-0006-05.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td>\n</tr>\n<tr>\n<td align=\"center\" valign=\"top\"><span class=\"Bold\">Figure A</span></td>\n</tr>\n</tbody>\n</table></div>" }

{ "type": "ul", "children": [ "If your prescribed AFREZZA dose is higher than 12 units, you will need to use more than 1 cartridge.\n", "If you need to use more than 1 cartridge for your dose, throw away the used cartridge before getting a new one. You can tell when a cartridge has been used, because the cup has moved to the center.\n", "\nDo not try to open the AFREZZA cartridges. The AFREZZA Inhaler opens the cartridge automatically during use.\n", "\nAFREZZA cartridges should only be used with the AFREZZA Inhaler. Do not try to breathe in the AFREZZA insulin powder in any other way. Do not put cartridges in your mouth and do not swallow cartridges.\n", "Use only 1 AFREZZA Inhaler at a time. The same inhaler should be used for the 4 unit, 8 unit or 12 unit cartridges.\n", "Store the inhaler in a clean, dry place with the mouthpiece cover on until your next dose.\n", "Throw away your AFREZZA Inhaler after 15 days and get a new one.\n" ], "text": "" }

If you are having problems with your AFREZZA Inhaler or if it breaks and you need a new one, call 1-877-323-8505.

{ "type": "p", "children": [], "text": "\nIf you are having problems with your AFREZZA Inhaler or if it breaks and you need a new one, call 1-877-323-8505.\n" }

Know your AFREZZA Inhaler:

{ "type": "p", "children": [], "text": "\nKnow your AFREZZA Inhaler:\n" }

Know your AFREZZA cartridges:

{ "type": "p", "children": [], "text": "\nKnow your AFREZZA cartridges:\n" }

<div class="scrollingtable"><table width="100%"> <col align="left" width="35.000%"/> <col align="left" width="65.000%"/> <tbody class="Headless"> <tr class="First"> <td align="left" colspan="2" valign="top"><span class="Bold">How to take your dose of AFREZZA:</span> <br/>Always be sure you have the right number of AFREZZA cartridges for your dose available before you start. AFREZZA cartridges must only be used with the AFREZZA Inhaler.<br/> </td> </tr> <tr> <td align="left" class="Botrule" colspan="2" valign="top"><span class="Bold">Step 1: Select the AFREZZA cartridges for your dose</span></td> </tr> <tr> <td align="center" class="Botrule" colspan="2" valign="top"><a name="f08"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-08.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td> </tr> <tr> <td align="left" colspan="2" valign="top"><span class="Bold">If your prescribed AFREZZA dose is more than 12 units</span> you will need to use <span class="Bold">more than 1 cartridge</span> to get your right dose.<br/> <br/> </td> </tr> <tr> <td align="center" class="Botrule" colspan="2" valign="top">Use the dosage chart below to determine the least number<br/>of AFREZZA cartridges you can use for your dose. Other<br/>cartridge combinations can be used.<br/> <br/> <a name="f09"></a><img alt="Figure B " src="/dailymed/image.cfm?name=afr01-0006-09.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/><span class="Bold">Figure B</span></td> </tr> <tr> <td align="left" class="Botrule" colspan="2" valign="top"> <br/> <br/> <a name="f10"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-10.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td> </tr> <tr> <td align="left" class="Botrule" colspan="2" valign="middle"><span class="Bold">Select Cartridges</span> <br/> <span class="Bold">Important: Use the AFREZZA dose chart above (see <a href="#f09">Figure B</a>)</span> to help you choose the right number of AFREZZA cartridges needed for your dose. </td> </tr> <tr> <td align="center" class="Botrule" valign="top"><a name="f11"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-11.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td><td align="left" class="Botrule" valign="top"><span class="Bold">Open Packages</span> <br/> <br/>Remove a blister card from the foil package.<br/>Tear along perforation to remove one strip. </td> </tr> <tr> <td align="center" class="Botrule" valign="top"><a name="f12"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-12.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td><td align="left" class="Botrule" valign="top"><span class="Bold">Push Cartridges to Remove</span> <br/>Remove a cartridge from the strip by pressing on the clear side to push the cartridge out. Remove the right number of cartridges for your dose. Pushing on the cup will not damage the cartridge.<br/> <span class="Bold">AFREZZA cartridges left over in an opened strip must be used within 3 days.</span></td> </tr> <tr> <td align="center" class="Botrule" colspan="2" valign="top"><a name="f13"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-13.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td> </tr> <tr class="Last"> <td align="left" class="Botrule" colspan="2" valign="top"><span class="Bold">Before Proceeding:</span> <br/>Check that you have the right AFREZZA cartridge(s) for your dose.<br/>Use only 1 inhaler for multiple cartridges. Throw away your AFREZZA Inhaler after 15 days and get a new one. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" width=\"35.000%\"/>\n<col align=\"left\" width=\"65.000%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">How to take your dose of AFREZZA:</span>\n<br/>Always be sure you have the right number of AFREZZA cartridges for your dose available before you start. AFREZZA cartridges must only be used with the AFREZZA Inhaler.<br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Step 1: Select the AFREZZA cartridges for your dose</span></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule\" colspan=\"2\" valign=\"top\"><a name=\"f08\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-08.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">If your prescribed AFREZZA dose is more than 12 units</span> you will need to use <span class=\"Bold\">more than 1 cartridge</span> to get your right dose.<br/>\n<br/>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule\" colspan=\"2\" valign=\"top\">Use the dosage chart below to determine the least number<br/>of AFREZZA cartridges you can use for your dose. Other<br/>cartridge combinations can be used.<br/>\n<br/>\n<a name=\"f09\"></a><img alt=\"Figure B\n\" src=\"/dailymed/image.cfm?name=afr01-0006-09.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/><span class=\"Bold\">Figure B</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule\" colspan=\"2\" valign=\"top\">\n<br/>\n<br/>\n<a name=\"f10\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-10.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule\" colspan=\"2\" valign=\"middle\"><span class=\"Bold\">Select Cartridges</span>\n<br/>\n<span class=\"Bold\">Important: Use the AFREZZA dose chart above (see <a href=\"#f09\">Figure B</a>)</span> to help you choose the right number of AFREZZA cartridges needed for your dose.\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule\" valign=\"top\"><a name=\"f11\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-11.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td><td align=\"left\" class=\"Botrule\" valign=\"top\"><span class=\"Bold\">Open Packages</span>\n<br/>\n<br/>Remove a blister card from the foil package.<br/>Tear along perforation to remove one strip.\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule\" valign=\"top\"><a name=\"f12\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-12.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td><td align=\"left\" class=\"Botrule\" valign=\"top\"><span class=\"Bold\">Push Cartridges to Remove</span>\n<br/>Remove a cartridge from the strip by pressing on the clear side to push the cartridge out. Remove the right number of cartridges for your dose. Pushing on the cup will not damage the cartridge.<br/>\n<span class=\"Bold\">AFREZZA cartridges left over in an opened strip must be used within 3 days.</span></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule\" colspan=\"2\" valign=\"top\"><a name=\"f13\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-13.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Before Proceeding:</span>\n<br/>Check that you have the right AFREZZA cartridge(s) for your dose.<br/>Use only 1 inhaler for multiple cartridges. Throw away your AFREZZA Inhaler after 15 days and get a new one.\n</td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table width="100%"> <col align="left" width="35.000%"/> <col align="left" width="65.000%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Step 2: Loading a cartridge</span></td> </tr> <tr> <td align="left" class="Botrule Lrule" valign="top"> <p class="First"> <a name="f14"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-14.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></p> </td><td align="left" class="Botrule Rrule" valign="top"><span class="Bold">Hold Inhaler</span> <br/> <br/>Hold the inhaler level in one (1) hand with the white mouthpiece on the top and purple base on the bottom.<br/> </td> </tr> <tr> <td align="left" class="Botrule Lrule" valign="top"> <p class="First"> <a name="f15"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-15.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></p> </td><td align="left" class="Botrule Rrule" valign="top"><span class="Bold">Open Inhaler</span> <br/> <br/>Open the inhaler by lifting the white mouthpiece to a vertical position.<br/>Before you put the AFREZZA cartridge in your inhaler, make sure it has been at <span class="Bold">room temperature for 10 minutes</span>. </td> </tr> <tr> <td align="left" class="Botrule Lrule" valign="top"> <p class="First"> <a name="f16"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-16.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></p> </td><td align="left" class="Botrule Rrule" valign="top"><span class="Bold">Place Cartridge</span> <br/> <br/>Hold the cartridge with the cup facing down.<br/> <br/>Line up the cartridge with the opening in the inhaler. The pointed end of the cartridge should line up with the pointed end in the inhaler.<br/>Place the cartridge into the inhaler. Be sure that the cartridge lies flat in the inhaler.<br/> <br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="2" valign="top"> <br/> <br/> <a name="f17"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-17.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/><span class="Bold">If any of these occur, throw away the cartridge</span> <br/> <span class="Bold">and load a new cartridge.</span> <br/> <br/> </td> </tr> <tr> <td align="center" class="Botrule Lrule" valign="top"><a name="f18"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-18.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td><td align="left" class="Botrule Rrule" valign="top"><span class="Bold">Close Inhaler</span> <br/> <br/>Lower the mouthpiece to close the inhaler (this will open the drug cartridge).<br/>You should feel a snap when the inhaler is closed. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Step 3: Inhaling AFREZZA</span></td> </tr> <tr> <td align="center" class="Botrule Lrule" valign="top"><a name="f19"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-19.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td><td align="left" class="Botrule Rrule" valign="top"><span class="Bold">Remove the Mouthpiece Cover</span> <br/> <br/> <span class="Bold">Important:</span> Keep the inhaler level during and after removal of the purple mouthpiece cover. </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="2" valign="top"> <br/> <a name="f20"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-20.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td> </tr> <tr> <td align="center" class="Botrule Lrule" valign="top"> <br/> <a name="f21"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-21.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td><td align="left" class="Botrule Rrule" valign="top"><span class="Bold">Exhale</span> <br/> <br/>Hold the inhaler away from your mouth and fully blow out (exhale). </td> </tr> <tr> <td align="center" class="Botrule Lrule" valign="top"><a name="f22"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-22.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td><td align="left" class="Botrule Rrule" valign="top"><span class="Bold">Position Inhaler in Mouth</span> <br/> <br/>Keeping your head level, place the mouthpiece in your mouth and <span class="Bold">tilt the inhaler down towards your chin, as shown.</span> <br/> <br/>Close your lips around the mouthpiece to form a seal.<br/> <br/> <br/> <span class="Bold">Tilt the inhaler downward while keeping your head level.</span> <br/> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule" valign="top"><a name="f23"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-23.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td><td align="left" class="Botrule Rrule" valign="top"><span class="Bold">Inhale Deeply and Hold Breath</span> <br/> <br/>With your mouth closed around the mouthpiece, <span class="Bold">inhale deeply through the inhaler</span>.<br/> <span class="Bold">Hold your breath</span> for as long as comfortable and at the same time remove the inhaler from your mouth. After holding your breath, exhale and continue to breathe normally.<br/> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" width=\"35.000%\"/>\n<col align=\"left\" width=\"65.000%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Step 2: Loading a cartridge</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule\" valign=\"top\">\n<p class=\"First\">\n<a name=\"f14\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-14.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></p>\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"><span class=\"Bold\">Hold Inhaler</span>\n<br/>\n<br/>Hold the inhaler level in one (1) hand with the white mouthpiece on the top and purple base on the bottom.<br/>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule\" valign=\"top\">\n<p class=\"First\">\n<a name=\"f15\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-15.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></p>\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"><span class=\"Bold\">Open Inhaler</span>\n<br/>\n<br/>Open the inhaler by lifting the white mouthpiece to a vertical position.<br/>Before you put the AFREZZA cartridge in your inhaler, make sure it has been at <span class=\"Bold\">room temperature for 10 minutes</span>.\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule\" valign=\"top\">\n<p class=\"First\">\n<a name=\"f16\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-16.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></p>\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"><span class=\"Bold\">Place Cartridge</span>\n<br/>\n<br/>Hold the cartridge with the cup facing down.<br/>\n<br/>Line up the cartridge with the opening in the inhaler. The pointed end of the cartridge should line up with the pointed end in the inhaler.<br/>Place the cartridge into the inhaler. Be sure that the cartridge lies flat in the inhaler.<br/>\n<br/>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<br/>\n<br/>\n<a name=\"f17\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-17.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/><span class=\"Bold\">If any of these occur, throw away the cartridge</span>\n<br/>\n<span class=\"Bold\">and load a new cartridge.</span>\n<br/>\n<br/>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule\" valign=\"top\"><a name=\"f18\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-18.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"><span class=\"Bold\">Close Inhaler</span>\n<br/>\n<br/>Lower the mouthpiece to close the inhaler (this will open the drug cartridge).<br/>You should feel a snap when the inhaler is closed.\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Step 3: Inhaling AFREZZA</span></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule\" valign=\"top\"><a name=\"f19\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-19.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"><span class=\"Bold\">Remove the Mouthpiece Cover</span>\n<br/>\n<br/>\n<span class=\"Bold\">Important:</span> Keep the inhaler level during and after removal of the purple mouthpiece cover.\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<br/>\n<a name=\"f20\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-20.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule\" valign=\"top\">\n<br/>\n<a name=\"f21\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-21.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"><span class=\"Bold\">Exhale</span>\n<br/>\n<br/>Hold the inhaler away from your mouth and fully blow out (exhale).\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule\" valign=\"top\"><a name=\"f22\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-22.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"><span class=\"Bold\">Position Inhaler in Mouth</span>\n<br/>\n<br/>Keeping your head level, place the mouthpiece in your mouth and <span class=\"Bold\">tilt the inhaler down towards your chin, as shown.</span>\n<br/>\n<br/>Close your lips around the mouthpiece to form a seal.<br/>\n<br/>\n<br/>\n<span class=\"Bold\">Tilt the inhaler downward while keeping your head level.</span>\n<br/>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Botrule Lrule\" valign=\"top\"><a name=\"f23\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-23.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"><span class=\"Bold\">Inhale Deeply and Hold Breath</span>\n<br/>\n<br/>With your mouth closed around the mouthpiece, <span class=\"Bold\">inhale deeply through the inhaler</span>.<br/>\n<span class=\"Bold\">Hold your breath</span> for as long as comfortable and at the same time remove the inhaler from your mouth. After holding your breath, exhale and continue to breathe normally.<br/>\n</td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table width="100%"> <col align="left" width="35.000%"/> <col align="left" width="65.000%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Step 4: Removing a used cartridge</span></td> </tr> <tr> <td align="center" class="Botrule Lrule" valign="top"><a name="f24"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-24.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td><td align="left" class="Botrule Rrule" valign="top"><span class="Bold">Replace Mouthpiece Cover</span> <br/> <br/>Place the purple mouthpiece cover back onto the inhaler. </td> </tr> <tr> <td align="center" class="Botrule Lrule" valign="top"><a name="f25"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-25.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td><td align="left" class="Botrule Rrule" valign="top"><span class="Bold">Open Inhaler</span> <br/> <br/>Open the inhaler by lifting up the white mouthpiece. </td> </tr> <tr> <td align="center" class="Botrule Lrule" valign="top"><a name="f26"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-26.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td><td align="left" class="Botrule Rrule" valign="top"><span class="Bold">Remove Cartridge</span> <br/>Remove the cartridge from the purple base. </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule" valign="top"><a name="f27"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-27.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td><td align="left" class="Botrule Rrule" valign="top"><span class="Bold">Throw away (or recycle) the Cartridge</span> <br/> <br/>Throw away the used cartridge in your regular household trash.<br/>Alternatively, the used cartridge (composed of HDPE, assigned recycling number 2) can be recycled. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" width=\"35.000%\"/>\n<col align=\"left\" width=\"65.000%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Step 4: Removing a used cartridge</span></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule\" valign=\"top\"><a name=\"f24\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-24.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"><span class=\"Bold\">Replace Mouthpiece Cover</span>\n<br/>\n<br/>Place the purple mouthpiece cover back onto the inhaler.\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule\" valign=\"top\"><a name=\"f25\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-25.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"><span class=\"Bold\">Open Inhaler</span>\n<br/>\n<br/>Open the inhaler by lifting up the white mouthpiece.\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule\" valign=\"top\"><a name=\"f26\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-26.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"><span class=\"Bold\">Remove Cartridge</span>\n<br/>Remove the cartridge from the purple base.\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Botrule Lrule\" valign=\"top\"><a name=\"f27\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-27.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\"><span class=\"Bold\">Throw away (or recycle) the Cartridge</span>\n<br/>\n<br/>Throw away the used cartridge in your regular household trash.<br/>Alternatively, the used cartridge (composed of HDPE, assigned recycling number 2) can be recycled.\n</td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table width="100%"> <col align="left" width="41.900%"/> <col align="left" width="58.100%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Multiple cartridge dosing</span></td> </tr> <tr> <td align="left" class="Botrule Lrule" valign="top"><span class="Bold">If you need more than one (1) AFREZZA cartridge for your dose, see the AFREZZA dosage chart above (<a href="#f09">Figure B</a>).</span> <br/> <br/> </td><td align="left" class="Botrule Rrule" valign="top"> <p class="First"> <a name="f28"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-28.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"> <br/> <span class="Bold">Repeat steps 2 through 4 for each AFREZZA cartridge you need for your prescribed AFREZZA dose.</span> <br/> <br/> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" colspan="2" valign="top"> <br/> <a name="f29"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-29.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" width=\"41.900%\"/>\n<col align=\"left\" width=\"58.100%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Multiple cartridge dosing</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule\" valign=\"top\"><span class=\"Bold\">If you need more than one (1) AFREZZA cartridge for your dose, see the AFREZZA dosage chart above (<a href=\"#f09\">Figure B</a>).</span>\n<br/>\n<br/>\n</td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<a name=\"f28\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-28.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<br/>\n<span class=\"Bold\">Repeat steps 2 through 4 for each AFREZZA cartridge you need for your prescribed AFREZZA dose.</span>\n<br/>\n<br/>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<br/>\n<a name=\"f29\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-29.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table width="100%"> <col align="left" width="100.000%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">How should I store AFREZZA?</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <br/> <a name="f30"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-30.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <br/> <a name="f31"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-31.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/><br/> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top"> <br/> <a name="f32"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-32.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" width=\"100.000%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Bold\">How should I store AFREZZA?</span></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<br/>\n<a name=\"f30\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-30.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<br/>\n<a name=\"f31\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-31.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/><br/>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<br/>\n<a name=\"f32\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-32.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table width="100%"> <col align="left" width="100.000%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Caring for your AFREZZA Inhaler:</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <a name="f33"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-33.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></p> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <a name="f34"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-34.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></p> </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <a name="f35"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-35.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" width=\"100.000%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Bold\">Caring for your AFREZZA Inhaler:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<a name=\"f33\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-33.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<a name=\"f34\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-34.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<a name=\"f35\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-35.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table width="100%"> <col align="left" width="5.000%"/> <col align="left" width="45.000%"/> <col align="left" width="25.000%"/> <col align="left" width="25.000%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="4" valign="middle"><span class="Bold">Switching between AFREZZA and injected insulin:</span></td> </tr> <tr> <td align="left" class="Botrule Lrule" valign="top"> <p class="First"> <a name="f36"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-36.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></p> </td><td align="left" class="Botrule Rrule" colspan="3" valign="top"><span class="Bold">Contact your healthcare provider before switching insulins.</span> <br/> <span class="Bold">AFREZZA is a mealtime insulin.</span> <br/> <span class="Bold">Do not switch from AFREZZA to a long acting insulin.</span> <br/> <span class="Bold">Do not switch from a long acting insulin to AFREZZA.</span></td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="middle"> <p class="First"> <a name="f37"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-37.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></p> </td><td align="left" class="Botrule Rrule" colspan="2" valign="top"> <p class="First"> <a name="f38"></a><img alt="Figure " src="/dailymed/image.cfm?name=afr01-0006-38.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10"/></p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" width=\"5.000%\"/>\n<col align=\"left\" width=\"45.000%\"/>\n<col align=\"left\" width=\"25.000%\"/>\n<col align=\"left\" width=\"25.000%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"4\" valign=\"middle\"><span class=\"Bold\">Switching between AFREZZA and injected insulin:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule\" valign=\"top\">\n<p class=\"First\">\n<a name=\"f36\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-36.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></p>\n</td><td align=\"left\" class=\"Botrule Rrule\" colspan=\"3\" valign=\"top\"><span class=\"Bold\">Contact your healthcare provider before switching insulins.</span>\n<br/>\n<span class=\"Bold\">AFREZZA is a mealtime insulin.</span>\n<br/>\n<span class=\"Bold\">Do not switch from AFREZZA to a long acting insulin.</span>\n<br/>\n<span class=\"Bold\">Do not switch from a long acting insulin to AFREZZA.</span></td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"middle\">\n<p class=\"First\">\n<a name=\"f37\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-37.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></p>\n</td><td align=\"left\" class=\"Botrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<a name=\"f38\"></a><img alt=\"Figure\n\" src=\"/dailymed/image.cfm?name=afr01-0006-38.jpg&amp;setid=29f4637b-e204-425b-b89c-7238008d8c10\"/></p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Manufactured by: MannKind CorporationDanbury, CT 06810

{ "type": "p", "children": [], "text": "Manufactured by: MannKind CorporationDanbury, CT 06810\n" }

US License No. #2190

{ "type": "p", "children": [], "text": "US License No. #2190\n" }

© 2016 – 2024 MannKind Corporation

{ "type": "p", "children": [], "text": "© 2016 – 2024 MannKind Corporation\n" }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration.\n" }

Revised: 11/2024

{ "type": "p", "children": [], "text": "Revised: 11/2024\n" }

AFREZZA is a registered trademark of MannKind Corporation

{ "type": "p", "children": [], "text": "AFREZZA is a registered trademark of MannKind Corporation\n" }

Patent: www.mannkindcorp.com/patent-notices

{ "type": "p", "children": [], "text": "Patent: www.mannkindcorp.com/patent-notices\n" }

Principal Display Panel 90 − 4 unit cartridges and 2 inhalers

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel 90 − 4 unit cartridges and 2 inhalers\n" }

NDC 47918-874-90

{ "type": "p", "children": [], "text": "NDC 47918-874-90\n" }

Rx ONLY

{ "type": "p", "children": [], "text": "Rx ONLY\n" }

afrezza®

{ "type": "p", "children": [], "text": "\nafrezza®\n" }

(insulin human)Inhalation Powder

{ "type": "p", "children": [], "text": "\n(insulin human)Inhalation Powder\n" }

4 units percartridge

{ "type": "p", "children": [], "text": "\n4 units percartridge\n" }

90 single-use cartridges

{ "type": "p", "children": [], "text": "\n90 single-use cartridges\n" }

FOR ORAL INHALATION ONLY

{ "type": "p", "children": [], "text": "\nFOR ORAL INHALATION ONLY\n" }

Carton Contains:

{ "type": "p", "children": [], "text": "Carton Contains:\n" }

90 – 4 unit cartridges + 2 inhalers

{ "type": "p", "children": [], "text": "\n90 – 4 unit cartridges + 2 inhalers\n" }

Dispense the enclosed Medication Guideto each patient

{ "type": "p", "children": [], "text": "Dispense the enclosed Medication Guideto each patient\n" }

mannkind®

{ "type": "p", "children": [], "text": "\nmannkind®\n" }

Principal Display Panel 90 – 8 unit cartridges and 2 inhalers

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel 90 – 8 unit cartridges and 2 inhalers\n" }

NDC 47918-878-90

{ "type": "p", "children": [], "text": "NDC 47918-878-90\n" }

Rx ONLY

{ "type": "p", "children": [], "text": "Rx ONLY\n" }

afrezza®

{ "type": "p", "children": [], "text": "\nafrezza®\n" }

(insulin human)Inhalation Powder

{ "type": "p", "children": [], "text": "\n(insulin human)Inhalation Powder\n" }

8 units percartridge

{ "type": "p", "children": [], "text": "\n8 units percartridge\n" }

90 single-use cartridges

{ "type": "p", "children": [], "text": "\n90 single-use cartridges\n" }

FOR ORAL INHALATION ONLY

{ "type": "p", "children": [], "text": "\nFOR ORAL INHALATION ONLY\n" }

Carton Contains:

{ "type": "p", "children": [], "text": "Carton Contains:\n" }

90 – 8 unit cartridges + 2 inhalers

{ "type": "p", "children": [], "text": "\n90 – 8 unit cartridges + 2 inhalers\n" }

Dispense the enclosed Medication Guideto each patient

{ "type": "p", "children": [], "text": "Dispense the enclosed Medication Guideto each patient\n" }

mannkind®

{ "type": "p", "children": [], "text": "\nmannkind®\n" }

Principal Display Panel 90 – 12 unit cartridges and 2 inhalers

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel 90 – 12 unit cartridges and 2 inhalers\n" }

NDC 47918-891-90

{ "type": "p", "children": [], "text": "NDC 47918-891-90\n" }

Rx ONLY

{ "type": "p", "children": [], "text": "Rx ONLY\n" }

afrezza®

{ "type": "p", "children": [], "text": "\nafrezza®\n" }

(insulin human)Inhalation Powder

{ "type": "p", "children": [], "text": "\n(insulin human)Inhalation Powder\n" }

12 units percartridge

{ "type": "p", "children": [], "text": "\n12 units percartridge\n" }

90 single-use cartridges

{ "type": "p", "children": [], "text": "\n90 single-use cartridges\n" }

FOR ORAL INHALATION ONLY

{ "type": "p", "children": [], "text": "\nFOR ORAL INHALATION ONLY\n" }

Carton Contains:

{ "type": "p", "children": [], "text": "Carton Contains:\n" }

90 – 12 unit cartridges + 2 inhalers

{ "type": "p", "children": [], "text": "\n90 – 12 unit cartridges + 2 inhalers\n" }

Dispense the enclosed Medication Guideto each patient

{ "type": "p", "children": [], "text": "Dispense the enclosed Medication Guideto each patient\n" }

mannkind®

{ "type": "p", "children": [], "text": "\nmannkind®\n" }

Principal Display Panel 180 cartridges; 60 – 4 unit cartridges, 60 – 8 unit cartridges and 60 – 12 unit cartridges and 2 inhalers (Titration Pack)

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel 180 cartridges; 60 – 4 unit cartridges, 60 – 8 unit cartridges and 60 – 12 unit cartridges and 2 inhalers (Titration Pack)\n" }

NDC 47918-902-18

{ "type": "p", "children": [], "text": "NDC 47918-902-18\n" }

Rx ONLY

{ "type": "p", "children": [], "text": "Rx ONLY\n" }

afrezza®

{ "type": "p", "children": [], "text": "\nafrezza®\n" }

(insulin human)Inhalation Powder

{ "type": "p", "children": [], "text": "\n(insulin human)Inhalation Powder\n" }

4 units percartridge

{ "type": "p", "children": [], "text": "\n4 units percartridge\n" }

8 units percartridge

{ "type": "p", "children": [], "text": "\n8 units percartridge\n" }

12 units percartridge

{ "type": "p", "children": [], "text": "\n12 units percartridge\n" }

180 single-use cartridges

{ "type": "p", "children": [], "text": "\n180 single-use cartridges\n" }

FOR ORAL INHALATION ONLY

{ "type": "p", "children": [], "text": "\nFOR ORAL INHALATION ONLY\n" }

Carton Contains:

{ "type": "p", "children": [], "text": "Carton Contains:\n" }

60 – 4 unit cartridges

{ "type": "p", "children": [], "text": "\n60 – 4 unit cartridges\n" }

60 – 8 unit cartridges

{ "type": "p", "children": [], "text": "\n60 – 8 unit cartridges\n" }

60 – 12 unit cartridges

{ "type": "p", "children": [], "text": "\n60 – 12 unit cartridges\n" }

2 - inhalers

{ "type": "p", "children": [], "text": "\n2 - inhalers\n" }

Dispense the enclosedMedication Guideto each patient

{ "type": "p", "children": [], "text": "Dispense the enclosedMedication Guideto each patient\n" }

mannkind®

{ "type": "p", "children": [], "text": "\nmannkind®\n" }

Principal Display Panel 180 cartridges; 90 – 4 unit cartridges and 90 – 8 unit cartridges and 2 inhalers (Titration Pack)

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel 180 cartridges; 90 – 4 unit cartridges and 90 – 8 unit cartridges and 2 inhalers (Titration Pack)\n" }

NDC 47918-880-18

{ "type": "p", "children": [], "text": "NDC 47918-880-18\n" }

Rx ONLY

{ "type": "p", "children": [], "text": "Rx ONLY\n" }

afrezza®

{ "type": "p", "children": [], "text": "\nafrezza®\n" }

(insulin human)Inhalation Powder

{ "type": "p", "children": [], "text": "\n(insulin human)Inhalation Powder\n" }

4 units percartridge

{ "type": "p", "children": [], "text": "\n4 units percartridge\n" }

8 units percartridge

{ "type": "p", "children": [], "text": "\n8 units percartridge\n" }

titration pack

{ "type": "p", "children": [], "text": "\ntitration pack\n" }

180 single-use cartridges

{ "type": "p", "children": [], "text": "\n180 single-use cartridges\n" }

FOR ORAL INHALATION ONLY

{ "type": "p", "children": [], "text": "\nFOR ORAL INHALATION ONLY\n" }

Carton Contains:

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90 – 4 unit cartridges

{ "type": "p", "children": [], "text": "\n90 – 4 unit cartridges\n" }

90 – 8 unit cartridges

{ "type": "p", "children": [], "text": "\n90 – 8 unit cartridges\n" }

2 - inhalers

{ "type": "p", "children": [], "text": "\n2 - inhalers\n" }

Dispense the enclosedMedication Guideto each patient

{ "type": "p", "children": [], "text": "Dispense the enclosedMedication Guideto each patient\n" }

mannkind®

{ "type": "p", "children": [], "text": "\nmannkind®\n" }

Principal Display Panel 180 cartridges; 90 – 8 unit cartridges and 90 – 12 unit cartridges and 2 inhalers

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel 180 cartridges; 90 – 8 unit cartridges and 90 – 12 unit cartridges and 2 inhalers\n" }

NDC 47918-898-18

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Rx ONLY

{ "type": "p", "children": [], "text": "Rx ONLY\n" }

afrezza®

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(insulin human)Inhalation Powder

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8 units percartridge

{ "type": "p", "children": [], "text": "\n8 units percartridge\n" }

12 units percartridge

{ "type": "p", "children": [], "text": "\n12 units percartridge\n" }

180 single-use cartridges

{ "type": "p", "children": [], "text": "\n180 single-use cartridges\n" }

FOR ORAL INHALATION ONLY

{ "type": "p", "children": [], "text": "\nFOR ORAL INHALATION ONLY\n" }

Carton Contains:

{ "type": "p", "children": [], "text": "Carton Contains:\n" }

90 – 8 unit cartridges

{ "type": "p", "children": [], "text": "\n90 – 8 unit cartridges\n" }

90 – 12 unit cartridges

{ "type": "p", "children": [], "text": "\n90 – 12 unit cartridges\n" }

2 - inhalers

{ "type": "p", "children": [], "text": "\n2 - inhalers\n" }

Dispense the enclosedMedication Guideto each patient

{ "type": "p", "children": [], "text": "Dispense the enclosedMedication Guideto each patient\n" }

mannkind®

{ "type": "p", "children": [], "text": "\nmannkind®\n" }

Principal Display Panel 27 cartridges; 9 – 4 unit cartridges, 9 – 8 unit cartridges and 9 – 12 unit cartridges and 1 inhaler (Sample Kit)

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel 27 cartridges; 9 – 4 unit cartridges, 9 – 8 unit cartridges and 9 – 12 unit cartridges and 1 inhaler (Sample Kit)\n" }

NDC 47918-903-27

{ "type": "p", "children": [], "text": "NDC 47918-903-27\n" }

Rx ONLY

{ "type": "p", "children": [], "text": "Rx ONLY\n" }

afrezza®

{ "type": "p", "children": [], "text": "\nafrezza®\n" }

(insulin human)Inhalation Powder

{ "type": "p", "children": [], "text": "\n(insulin human)Inhalation Powder\n" }

4 units percartridge

{ "type": "p", "children": [], "text": "\n4 units percartridge\n" }

8 units percartridge

{ "type": "p", "children": [], "text": "\n8 units percartridge\n" }

12 units percartridge

{ "type": "p", "children": [], "text": "\n12 units percartridge\n" }

27 single-use cartridges

{ "type": "p", "children": [], "text": "\n27 single-use cartridges\n" }

FOR ORAL INHALATION ONLY

{ "type": "p", "children": [], "text": "\nFOR ORAL INHALATION ONLY\n" }

Carton Contains:

{ "type": "p", "children": [], "text": "Carton Contains:\n" }

9 – 4 unit cartridges

{ "type": "p", "children": [], "text": "\n9 – 4 unit cartridges\n" }

9 – 8 unit cartridges

{ "type": "p", "children": [], "text": "\n9 – 8 unit cartridges\n" }

9 – 12 unit cartridges

{ "type": "p", "children": [], "text": "\n9 – 12 unit cartridges\n" }

1 - inhaler

{ "type": "p", "children": [], "text": "\n1 - inhaler\n" }

Dispense the enclosedMedication Guideto each patient

{ "type": "p", "children": [], "text": "Dispense the enclosedMedication Guideto each patient\n" }

mannkind®

{ "type": "p", "children": [], "text": "\nmannkind®\n" }

Principal Display Panel 30 cartridges;15 – 4 unit cartridges and 15 – 8 unit cartridges (Sample Kit)

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel 30 cartridges;15 – 4 unit cartridges and 15 – 8 unit cartridges (Sample Kit)\n" }

NDC 47918-904-30

{ "type": "p", "children": [], "text": "NDC 47918-904-30\n" }

Rx ONLY

{ "type": "p", "children": [], "text": "Rx ONLY\n" }

afrezza®

{ "type": "p", "children": [], "text": "\nafrezza®\n" }

(insulin human)Inhalation Powder

{ "type": "p", "children": [], "text": "\n(insulin human)Inhalation Powder\n" }

4 units percartridge

{ "type": "p", "children": [], "text": "\n4 units percartridge\n" }

8 units percartridge

{ "type": "p", "children": [], "text": "\n8 units percartridge\n" }

30 single-use cartridges

{ "type": "p", "children": [], "text": "\n30 single-use cartridges\n" }

FOR ORAL INHALATION ONLY

{ "type": "p", "children": [], "text": "\nFOR ORAL INHALATION ONLY\n" }

Carton Contains:

{ "type": "p", "children": [], "text": "Carton Contains:\n" }

15 – 4 unit cartridges

{ "type": "p", "children": [], "text": "\n15 – 4 unit cartridges\n" }

15 – 8 unit cartridges

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1 - inhaler

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Dispense the enclosedMedication Guideto each patient

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mannkind®

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NOVOLOG MIX 70/30 is a mixture of insulin aspart protamine and insulin aspart indicated to improve glycemic control in adult patients with diabetes mellitus.

{ "type": "p", "children": [], "text": "NOVOLOG MIX 70/30 is a mixture of insulin aspart protamine and insulin aspart indicated to improve glycemic control in adult patients with diabetes mellitus." }

Limitations of Use:

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{ "type": "ul", "children": [ "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." ], "text": "" }

Dosage modification may be needed when NOVOLOG MIX 70/30 is used concomitantly with certain drugs [see Drug Interactions (7)].

Injectable suspension: 100 units/mL (U-100) of NOVOLOG MIX 70/30, 70% insulin aspart protamine and 30% insulin aspart, is a white and cloudy suspension available as:

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{ "type": "ul", "children": [ "3 mL single-patient-use FlexPen prefilled pen" ], "text": "" }

NOVOLOG MIX 70/30 is contraindicated:

{ "type": "p", "children": [], "text": "NOVOLOG MIX 70/30 is contraindicated:" }

{ "type": "ul", "children": [ "During episodes of hypoglycemia\n \n [\n \n see Warnings and Precautions (5.3)]\n \n \n", "In patients with hypersensitivity to NOVOLOG MIX 70/30 or one of its excipients\n \n [see Warnings and Precautions (5.5)]\n" ], "text": "" }

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 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.

Hypoglycemia is the most common adverse reaction of all insulins, 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 insulins, 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 concomitantly 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 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 insulins, 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 insulins, 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.

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:

Common adverse reactions were defined as events that occurred in ≥5%, excluding hypoglycemia, of the population studied. Common adverse reactions that occurred for NOVOLOG MIX 70/30-treated patients with type 1 diabetes mellitus and type 2 diabetes mellitus 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 that Occurred in ≥ 5% of Type 1 Diabetes Mellitus Adult Patients Treated with NOVOLOG MIX 70/30

<div class="scrollingtable"><table width="68%"> <col width="42%"/> <col width="27%"/> <col width="10%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">NOVOLOG MIX 70/30</span> </p> <p> <span class="Bold">(n=55)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Preferred Term</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">%</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypoglycemia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">38</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">69</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Headache</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">19</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">35</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Influenza-like symptoms</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dyspepsia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Back pain</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diarrhea</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pharyngitis</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rhinitis</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Skeletal pain</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Upper respiratory tract infection</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td> </tr> </tbody> </table></div>

Table 2: Adverse Reactions that Occurred in ≥ 5% of Type 2 Diabetes Mellitus Adult Patients Treated with NOVOLOG MIX 70/30

<div class="scrollingtable"><table width="67.32%"> <col width="42%"/> <col width="26%"/> <col width="9%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">NOVOLOG MIX 70/30</span> </p> <p> <span class="Bold">(n=85)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Preferred Term</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">N</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">%</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Hypoglycemia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">40</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">47</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Upper respiratory tract infection</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Headache</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diarrhea</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Neuropathy</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pharyngitis</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Abdominal pain</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rhinitis</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5</p> </td> </tr> </tbody> </table></div>

Severe Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including NOVOLOG MIX 70/30 .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.

Adverse Reactions Associated with 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 insulins, including NOVOLOG MIX 70/30, and has been attributed to the anabolic effects of insulin and the decrease in glycosuria.

Peripheral Edema

Insulins, 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 patients 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 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.

Localized cutaneous amyloidosis at the injection site has occurred with insulin aspart. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.

The table below presents clinically significant drug interactions with NOVOLOG MIX 70/30.

{ "type": "p", "children": [], "text": "The table below presents clinically significant drug interactions with NOVOLOG MIX 70/30." }

Table 3: Clinically Significant Drug Interactions with NOVOLOG MIX 70/30

{ "type": "p", "children": [], "text": "\nTable 3: Clinically Significant Drug Interactions with NOVOLOG MIX 70/30\n" }

<div class="scrollingtable"><table width="100%"> <col width="22%"/> <col width="78%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Drugs that May Increase the Risk of Hypoglycemia</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Drugs:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">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</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is concomitantly administered with these drugs.</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Drugs that May Decrease the Blood Glucose Lowering Effect of NOVOLOG MIX 70/30</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Drugs:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is concomitantly administered with these drugs.</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of NOVOLOG MIX 70/30</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Drugs:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is concomitantly administered with these drugs.</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Drugs that May Blunt Signs and Symptoms of Hypoglycemia</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Drugs:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Beta-blockers, clonidine, guanethidine, and reserpine</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is concomitantly administered with these drugs.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"22%\"/>\n<col width=\"78%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Drugs that May Increase the Risk of Hypoglycemia</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Drugs:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">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</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is concomitantly administered with these drugs.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Drugs that May Decrease the Blood Glucose Lowering Effect of NOVOLOG MIX 70/30</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Drugs:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">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.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is concomitantly administered with these drugs.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of NOVOLOG MIX 70/30</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Drugs:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is concomitantly administered with these drugs.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Drugs that May Blunt Signs and Symptoms of Hypoglycemia</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Drugs:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Beta-blockers, clonidine, guanethidine, and reserpine</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is concomitantly administered with these drugs.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

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 ndtrimester 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.

Risk Summary

There are no data on the presence of NOVOLOG MIX 70/30 in human milk, the effects on the breastfed infant, or the effect on milk production. One small published study reported that exogenous insulin, including insulin aspart, was present in human milk. However, there is insufficient information to determine the effects of insulin aspart on the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NOVOLOG MIX 70/30, and any potential adverse effects on the breastfed infant from NOVOLOG MIX 70/30, or from the underlying maternal condition.

Safety and effectiveness of NOVOLOG MIX 70/30 have not been established in pediatric patients with diabetes mellitus.

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 adult patients. In geriatric patients with diabetes, the initial dosing, dose increments should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in geriatric patients.

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.

{ "type": "p", "children": [], "text": "Excess insulin administration may cause hypoglycemia and hypokalemia\n \n [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.\n\n " }

Insulin aspart protamine and insulin aspart is a human insulin analog containing 70% insulin aspart protamine crystals and 30% soluble insulin aspart. 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 has the empirical formula C 256H 381N 65O 79S 6and a molecular weight of 5825.8 Da.

{ "type": "p", "children": [], "text": "Insulin aspart protamine and insulin aspart is a human insulin analog containing 70% insulin aspart protamine crystals and 30% soluble insulin aspart. 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\n \n Saccharomyces cerevisiae(baker’s yeast). Insulin aspart has the empirical formula C\n \n 256H\n \n 381N\n \n 65O\n \n 79S\n \n 6and a molecular weight of 5825.8 Da.\n\n " }

Figure 1. Structural formula of insulin aspart

{ "type": "p", "children": [], "text": "\nFigure 1. Structural formula of insulin aspart\n" }

NOVOLOG MIX 70/30 (insulin aspart protamine and insulin aspart) is a uniform, white and cloudy, sterile injectable suspension for subcutaneous use. Each mL contains 100 units of insulin aspart and the inactive ingredients: disodium hydrogen phosphate dihydrate (1.25 mg), glycerol (16.0 mg), metacresol (1.72 mg), phenol (1.50 mg), protamine sulfate (0.32 mg), sodium chloride (0.877 mg), zinc (19.6 mcg), and Water for Injection, USP. NOVOLOG MIX 70/30 has a pH of 7.20 - 7.44. Hydrochloric acid or sodium hydroxide may be added to adjust pH.

{ "type": "p", "children": [], "text": "NOVOLOG MIX 70/30 (insulin aspart protamine and insulin aspart) is a uniform, white and cloudy, sterile injectable suspension for subcutaneous use. Each mL contains 100 units of insulin aspart and the inactive ingredients: disodium hydrogen phosphate dihydrate (1.25 mg), glycerol (16.0 mg), metacresol (1.72 mg), phenol (1.50 mg), protamine sulfate (0.32 mg), sodium chloride (0.877 mg), zinc (19.6 mcg), and Water for Injection, USP. 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 of NOVOLOG MIX 70/30, the onset of action is between 10-20 minutes and the mean ± SD time to peak activity is 2.7 hr ± 0.9 hr. The duration of action may be as long as 24 hours (see Figure 2).

Figure 2. Pharmacodynamic Activity Profile of NOVOLOG MIX 70/30 in healthy subjects after a 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 rapidly from the subcutaneous layer. 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 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 (C max) 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 profile).

Figure 3. Pharmacokinetic Profile of NOVOLOG MIX 70/30 after a 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 vivomicronucleus 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 a three-month, open-label trial, adult patients with type 1 (n=104) or type 2 (n=187) diabetes mellitus 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 1cwere comparable across the treatment groups (see Table 4).

For patients with type 1 diabetes mellitus (T1DM) the mean age was 43 years old, 64% were male, 100% were White, the mean body mass index (BMI) was 26.1 kg/m 2, and mean duration of diabetes mellitus was 15 years. For patients with type 2 diabetes mellitus (T2DM), the mean age was 63 years old, 54% were male, 100% were White, the BMI 28.1 kg/m 2, and the mean duration of diabetes mellitus was 15 years.

Table 4: Glycemic Parameters at the End of Treatment [Mean ± SD (n subjects)]

<div class="scrollingtable"><table width="100%"> <col width="45%"/> <col width="28%"/> <col width="27%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">NOVOLOG MIX 70/30</span> </p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">Novolin 70/30</span> </p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Type 1, n=104</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule" valign="top"></td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Fasting Blood Glucose (mg/dL)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">174 ± 64 (48)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">142 ± 59 (44)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">1.5 Hour Post Breakfast (mg/dL)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">187 ± 82 (48)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">200 ± 82 (42)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">1.5 Hour Post Dinner (mg/dL)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">162 ± 77 (47)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">171 ± 66 (41)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">HbA <span class="Sub">1c</span>(%) Baseline </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8.4 ± 1.2 (51)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">8.5 ± 1.1 (46)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">HbA <span class="Sub">1c</span>(%) Week 12 </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8.4 ± 1.1 (51)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">8.3 ± 1.0 (47)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Type 2, n=187</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule" valign="top"></td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Fasting Blood Glucose (mg/dL)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">153 ± 40 (76)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">152 ± 69 (93)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">1.5 Hour Post Breakfast (mg/dL)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">182 ± 65 (75)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">200 ± 80 (92)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">1.5 Hour Post Dinner (mg/dL)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">168 ± 51 (75)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">191 ± 65 (93)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">HbA <span class="Sub">1c</span>(%) Baseline </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8.1 ± 1.2 (82)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">8.2 ± 1.3 (98)</p> </td> </tr> <tr class="Last"> <td class="Botrule Rrule" valign="top"> <p class="First">HbA <span class="Sub">1c</span>(%) Week 12 </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7.9 ± 1.0 (81)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">8.1 ± 1.1 (96)</p> </td> </tr> </tbody> </table></div>

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.

Trial 1:

In a 34-week, open-label trial (Trial 1), insulin-naïve patients with type 2 diabetes mellitus currently treated with 2 oral antidiabetic agents were switched to treatment with metformin and pioglitazone. The mean age of the trial population was 53 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 2,500 mg per day and 30 or 45 mg per day, respectively. After the optimization period, patients 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 international units 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 international units.

Table 5: Combination Therapy with Metformin and Pioglitazone in Patients with Type 2 Diabetes Mellitus [Mean (SD)] (Trial 1)

<div class="scrollingtable"><table width="100%"> <col width="54%"/> <col width="24%"/> <col width="22%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Treatment duration 24-weeks</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">NOVOLOG MIX 70/30 + Metformin</span> </p> <p> <span class="Bold">+ Pioglitazone</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Metformin + Pioglitazone</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">HbA <span class="Sub">1c</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Baseline mean ± SD (n)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8.1 ± 1.0 (102)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8.1 ± 1.0 (98)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">End-of-study mean ± SD (n) - LOCF</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6.6 ± 1.0 (93)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7.8 ± 1.2 (87)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Adjusted Mean change from baseline ± SE (n)*</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-1.6 ± 0.1 (93)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-0.3 ± 0.1 (87)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Treatment difference mean ± SE* 95% CI*</p> </td><td align="center" class="Botrule Rrule" colspan="2" valign="top"> <p class="First">-1.3 ± 0.1</p> <p>(-1.6, -1.0)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Percentage of subjects reaching HbA <span class="Sub">1c</span>&lt;7.0% </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">76%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">24%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Percentage of subjects reaching HbA <span class="Sub">1c</span>≤6.5% </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">59%</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fasting Blood Glucose (mg/dL)</p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Baseline Mean ± SD (n)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">173 ± 39.8 (93)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">163 ± 35.4 (88)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">End of Study Mean ± SD (n) - LOCF</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">130 ± 50.0 (90)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">162 ± 40.8 (84)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Adjusted Mean change from baseline ± SE (n)*</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-43.0 ± 5.3 (90)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-3.9 ± 5.3 (84)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">End-of-Study Blood Glucose (Plasma) (mg/dL)</p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">2 Hour Post Breakfast</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">138 ± 42.8 (86)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">188 ± 57.7 (74)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">2 Hour Post Lunch</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">150 ± 41.5 (86)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">176 ± 56.5 (74)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">2 Hour Post Dinner</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">141 ± 57.8 (86)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">195 ± 60.1 (74)</p> </td> </tr> </tbody> </table></div>

Table 6:Combination Therapy with Metformin ± Pioglitazone and Two Types of Insulin in Patients with Type 2 Diabetes Mellitus [Mean (SD)] (Trial 2)

<div class="scrollingtable"><table width="100%"> <col width="51%"/> <col width="25%"/> <col width="24%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Treatment duration 28-weeks</span> </p> </td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">NOVOLOG  MIX 70/30 + Metformin ± Pioglitazone</span> </p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">Insulin Glargine + Metformin ± Pioglitazone</span> </p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Number of patients</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">117</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">116</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">HbA <span class="Sub">1c</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule" valign="top"></td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Baseline mean (%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9.7 ± 1.5 (117)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">9.8 ± 1.4 (114)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">End-of-study mean (± SD)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6.9 ± 1.2 (108)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">7.4 ± 1.2 (114)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Mean change from baseline</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">-2.7 ± 1.6 (108)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">-2.4 ± 1.5 (114)</p> </td> </tr> <tr class="Last"> <td class="Botrule Rrule" valign="top"> <p class="First">Percentage of subjects reaching HbA <span class="Sub">1c</span>&lt;7.0% </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">66%</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">40%</p> </td> </tr> </tbody> </table></div>

NOVOLOG MIX 70/30 (insulin aspart protamine and insulin aspart) is a white and cloudy injectable suspension containing 100 units/mL (U-100) of 70% insulin aspart protamine and 30% insulin aspart available as:

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The NOVOLOG MIX 70/30 FlexPen dials in 1-unit increments.

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NDC: 70518-2119-00

{ "type": "p", "children": [], "text": "NDC: 70518-2119-00" }

PACKAGING: 5 in 1 CARTON, 3 mL in 1 SYRINGE PLASTIC TYPE 2

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Dispense in the original sealed carton with the enclosed Instructions for Use. Store unused NOVOLOG MIX 70/30 in a refrigerator between 2°C to 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.

{ "type": "p", "children": [], "text": "Dispense in the original sealed carton with the enclosed Instructions for Use. Store unused NOVOLOG MIX 70/30 in a refrigerator between 2°C to 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.

{ "type": "p", "children": [], "text": "Always remove the needle after each injection and store NOVOLOG MIX 70/30 FlexPen without a needle attached." }

Not in-use (unopened) Room Temperature (up to 30°C [86°F]): 14 days

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Not in-use (unopened) Refrigerated (2°C to 8°C [36°F  46°F]): until expiration date

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In-use (opened) Room Temperature (up to 30°C [86°F]): 14 days (Do not refrigerate)

{ "type": "p", "children": [], "text": "In-use (opened) Room Temperature (up to 30°C [86°F]): 14 days (Do not refrigerate)" }

Repackaged and Distributed By:

{ "type": "p", "children": [], "text": "Repackaged and Distributed By:" }

Remedy Repack, Inc.

{ "type": "p", "children": [], "text": "Remedy Repack, Inc." }

625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

{ "type": "p", "children": [], "text": "625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762" }

Advise the patient to read the FDA-approved patient labeling(Patient Information and Instructions for Use).

{ "type": "p", "children": [], "text": "Advise the patient to read the \n FDA-approved patient labeling(Patient Information and Instructions for Use).\n " }

Never Share a NOVOLOG MIX 70/30 FlexPen between Patients

{ "type": "p", "children": [], "text": "\nNever Share a NOVOLOG MIX 70/30 FlexPen between Patients\n" }

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)].

{ "type": "p", "children": [], "text": "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 \n [see Warnings and Precautions (5.1)]. \n \n" }

Hyperglycemia or Hypoglycemia

{ "type": "p", "children": [], "text": "\nHyperglycemia or Hypoglycemia\n" }

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)].

{ "type": "p", "children": [], "text": "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 \n [see Warnings and Precautions (5.3)].\n " }

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.

{ "type": "p", "children": [], "text": "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)] .

{ "type": "p", "children": [], "text": "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 \n [see Warnings and Precautions (5.2)] \n .\n " }

Hypoglycemia with Medication Errors

{ "type": "p", "children": [], "text": "\nHypoglycemia with Medication Errors\n" }

Instruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Instruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products \n [see Warnings and Precautions (5.4)].\n " }

Hypersensitivity Reactions

{ "type": "p", "children": [], "text": "\nHypersensitivity Reactions\n" }

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)].

{ "type": "p", "children": [], "text": "Advise patients that hypersensitivity reactions have occurred with NOVOLOG MIX 70/30. Inform patients of the symptoms of hypersensitivity reactions \n [see Warnings and Precautions (5.5)].\n " }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Novo Nordisk Inc.

{ "type": "p", "children": [], "text": "Novo Nordisk Inc." }

800 Scudders Mill Road

{ "type": "p", "children": [], "text": "800 Scudders Mill Road" }

Plainsboro, NJ 08536

{ "type": "p", "children": [], "text": "Plainsboro, NJ 08536" }

U.S. License Number 1261

{ "type": "p", "children": [], "text": "U.S. License Number 1261" }

Version: 18

{ "type": "p", "children": [], "text": "Version: 18" }

Novo Nordisk ®, NOVOLOG ®, FlexPen ®, and Novolin ®are registered trademarks of Novo Nordisk ®A/S.

{ "type": "p", "children": [], "text": "\nNovo Nordisk \n ®, NOVOLOG \n ®, FlexPen \n ®, and Novolin \n ®are registered trademarks of Novo Nordisk \n ®A/S. \n \n" }

ReliOn ® is a registered trademark of Walmart Inc. and is used under license by Novo Nordisk Inc.

{ "type": "p", "children": [], "text": "\nReliOn \n ® is a registered trademark of Walmart Inc. and is used under license by Novo Nordisk Inc. \n \n" }

Patent Information: http://novonordisk-us.com/products/product-patents.html

{ "type": "p", "children": [], "text": "Patent Information: \n http://novonordisk-us.com/products/product-patents.html\n" }

© 2023 Novo Nordisk

{ "type": "p", "children": [], "text": "© 2023 Novo Nordisk" }

For additional information about NOVOLOG MIX 70/30 contact:

{ "type": "p", "children": [], "text": "For additional information about NOVOLOG MIX 70/30 contact:" }

www.novonordisk-us.com

{ "type": "p", "children": [], "text": "\nwww.novonordisk-us.com\n" }

Repackaged By / Distributed By: RemedyRepack Inc.

{ "type": "p", "children": [], "text": "Repackaged By / Distributed By: RemedyRepack Inc." }

625 Kolter Drive, Indiana, PA 15701

{ "type": "p", "children": [], "text": "625 Kolter Drive, Indiana, PA 15701" }

(724) 465-8762

{ "type": "p", "children": [], "text": "(724) 465-8762" }

<div class="scrollingtable"><table width="100%"> <col width="33%"/> <col width="10%"/> <col width="13%"/> <col width="5%"/> <col width="39%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="5" valign="top"> <p class="First"> <span class="Bold">NovoLog <span class="Sup">®</span>Mix 70/30 </span>(NŌ-vō-log-MIX-SEV-en-tee-THIR-tee) </p> <p>(insulin aspart protamine and insulin aspart)</p> <p>injectable suspension, for subcutaneous use</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">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.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">What is NovoLog Mix 70/30?</span> </p> <ul> <li>NovoLog Mix 70/30 is a man-made insulin that is used to control high blood sugar in people with diabetes mellitus.</li> <li>It is not known if NovoLog Mix 70/30 is safe and effective in children.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Who should not take NovoLog Mix 70/30?</span> </p> <p> <span class="Bold">Do not take NovoLog Mix 70/30 if you:</span> </p> <ul> <li>are having an episode of low blood sugar (hypoglycemia).</li> <li>have an allergy to NovoLog Mix 70/30 or any of the ingredients in NovoLog Mix 70/30.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Before taking NovoLog Mix 70/30, tell your healthcare provider about all your medical conditions including, if you are:</span> </p> <ul> <li>pregnant, planning to become pregnant, or are breastfeeding.</li> <li>taking new prescription or over-the-counter medicines, vitamins, or herbal supplements.</li> </ul> <p> <span class="Bold">Before you start taking NovoLog Mix 70/30, talk to your healthcare provider about low blood sugar and how to manage it.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">How should I take NovoLog Mix 70/30?</span> </p> <ul> <li> <span class="Bold">Read the Instructions for Use</span>that come with your NovoLog Mix 70/30. </li> <li>Take NovoLog Mix 70/30 exactly as your healthcare provider tells you to.</li> <li> <span class="Bold">NovoLog Mix 70/30 starts acting fast. If you have Type 1 diabetes, inject it up to 15 minutes before you eat a meal.</span>Do not inject NovoLog Mix 70/30 if you are not planning to eat within 15 minutes. <span class="Bold">If you have Type 2 diabetes, you may inject NovoLog Mix 70/30 up to 15 minutes before or after starting your meal.</span> </li> <li> <span class="Bold">Do not mix</span>NovoLog Mix 70/30 with other insulin products <span class="Bold">or</span>use in an insulin pump. </li> <li>Know the type and strength of insulin you take. <span class="Bold">Do not</span>change the type of insulin you take unless your healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin may need to change if you take different types of insulin. </li> <li> <span class="Bold">Check your blood sugar levels.</span>Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels. </li> <li> <span class="Bold">Do not reuse or share your needles or syringes with other people.</span>You may give other people a serious infection or get a serious infection from them. </li> <li>NovoLog Mix 70/30 is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs, or upper arms.</li> <li> <span class="Bold">Change (rotate) your injection sites within the same area you choose with each dose</span>to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. <ul> <li> <span class="Bold">Do not</span>use the exact same spot for each injection. </li> <li> <span class="Bold">Do not</span>inject where skin has pits, is thickened, or has lumps. </li> <li> <span class="Bold">Do not</span>inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. </li> </ul> </li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">What should I avoid while taking NovoLog Mix 70/30?</span> </p> <p> <span class="Bold">While taking NovoLog Mix 70/30 do not:</span> </p> <ul> <li>Drive or operate heavy machinery, until you know how NovoLog Mix 70/30 affects you.</li> <li>Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">What are the possible side effects of NovoLog Mix 70/30?</span> </p> <p> <span class="Bold">NovoLog Mix 70/30 may cause serious side effects that can lead to death, including:</span> </p> <p> <span class="Bold">Low blood sugar (hypoglycemia).</span>Signs and symptoms that may indicate low blood sugar include: </p> </td> </tr> <tr> <td class="Lrule" valign="top"> <ul> <li>dizziness or light-headedness</li> </ul> </td><td colspan="2" valign="top"> <ul> <li>blurred vision</li> </ul> </td><td class="Rrule" colspan="2" valign="top"> <ul> <li>anxiety, irritability, or mood changes</li> </ul> </td> </tr> <tr> <td class="Lrule" valign="top"> <ul> <li>sweating</li> </ul> </td><td colspan="2" valign="top"> <ul> <li>slurred speech</li> </ul> </td><td class="Rrule" colspan="2" valign="top"> <ul> <li>hunger</li> </ul> </td> </tr> <tr> <td class="Lrule" valign="top"> <ul> <li>confusion</li> </ul> </td><td colspan="2" valign="top"> <ul> <li>shakiness</li> </ul> </td><td class="Rrule" colspan="2" valign="top"></td> </tr> <tr> <td class="Lrule" valign="top"> <ul> <li>headache</li> </ul> </td><td colspan="2" valign="top"> <ul> <li>fast heart beat</li> </ul> </td><td class="Rrule" colspan="2" valign="top"></td> </tr> <tr> <td class="Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Your insulin dose may need to change because of:</span> </p> </td> </tr> <tr> <td class="Lrule" colspan="2" valign="top"> <ul> <li>change in level of physical activity or exercise</li> </ul> </td><td colspan="2" valign="top"> <ul> <li>increased stress</li> </ul> </td><td class="Rrule" valign="top"> <ul> <li>change in diet</li> </ul> </td> </tr> <tr> <td class="Lrule" colspan="2" valign="top"> <ul> <li>weight gain or loss</li> </ul> </td><td colspan="2" valign="top"> <ul> <li>illness</li> </ul> </td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Other common side effects of NovoLog Mix 70/30 may include:</span> </p> <ul> <li>low potassium in your blood (hypokalemia), reactions at the injection site, itching, rash, serious allergic reactions (whole body reactions), skin thickening or pits at the injection site (lipodystrophy), weight gain, and swelling of your hands and feet.</li> </ul> <p> <span class="Bold">Get emergency medical help if you have:</span> </p> <ul> <li>trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion.</li> </ul> <p>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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">General information about the safe and effective use of NovoLog Mix 70/30.</span> </p> <p>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.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="5" valign="top"> <p class="First"> <span class="Bold">What are the ingredients in NovoLog Mix 70/30?</span> </p> <p> <span class="Bold">Active Ingredient:</span>70% insulin aspart protamine and 30% insulin aspart. </p> <p> <span class="Bold">Inactive Ingredients</span>: disodium hydrogen phosphate dihydrate, glycerol, metacresol, phenol, protamine sulfate, sodium chloride, zinc, and Water for Injection, USP. Hydrochloric acid or sodium hydroxide may be added to adjust pH. </p> <p> <span class="Bold">Manufactured by:</span>Novo Nordisk Inc., Plainsboro, NJ 08536 U.S. License Number 1261 </p> <p>For more information, go to www.novonordisk-us.com or call 1-800-727-6500.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"33%\"/>\n<col width=\"10%\"/>\n<col width=\"13%\"/>\n<col width=\"5%\"/>\n<col width=\"39%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"5\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">NovoLog\n \n <span class=\"Sup\">®</span>Mix 70/30\n \n </span>(NŌ-vō-log-MIX-SEV-en-tee-THIR-tee)\n \n </p>\n<p>(insulin aspart protamine and insulin aspart)</p>\n<p>injectable suspension, for subcutaneous use</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"5\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">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.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"5\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is NovoLog Mix 70/30?</span>\n</p>\n<ul>\n<li>NovoLog Mix 70/30 is a man-made insulin that is used to control high blood sugar in people with diabetes mellitus.</li>\n<li>It is not known if NovoLog Mix 70/30 is safe and effective in children.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"5\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Who should not take NovoLog Mix 70/30?</span>\n</p>\n<p>\n<span class=\"Bold\">Do not take NovoLog Mix 70/30 if you:</span>\n</p>\n<ul>\n<li>are having an episode of low blood sugar (hypoglycemia).</li>\n<li>have an allergy to NovoLog Mix 70/30 or any of the ingredients in NovoLog Mix 70/30.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"5\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Before taking NovoLog Mix 70/30, tell your healthcare provider about all your medical conditions including, if you are:</span>\n</p>\n<ul>\n<li>pregnant, planning to become pregnant, or are breastfeeding.</li>\n<li>taking new prescription or over-the-counter medicines, vitamins, or herbal supplements.</li>\n</ul>\n<p>\n<span class=\"Bold\">Before you start taking NovoLog Mix 70/30, talk to your healthcare provider about low blood sugar and how to manage it.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"5\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I take NovoLog Mix 70/30?</span>\n</p>\n<ul>\n<li>\n<span class=\"Bold\">Read the Instructions for Use</span>that come with your NovoLog Mix 70/30.\n \n </li>\n<li>Take NovoLog Mix 70/30 exactly as your healthcare provider tells you to.</li>\n<li>\n<span class=\"Bold\">NovoLog Mix 70/30 starts acting fast. If you have Type 1 diabetes, inject it up to 15 minutes before you eat a meal.</span>Do not inject NovoLog Mix 70/30 if you are not planning to eat within 15 minutes.\n \n <span class=\"Bold\">If you have Type 2 diabetes, you may inject NovoLog Mix 70/30 up to 15 minutes before or after starting your meal.</span>\n</li>\n<li>\n<span class=\"Bold\">Do not mix</span>NovoLog Mix 70/30 with other insulin products\n \n <span class=\"Bold\">or</span>use in an insulin pump.\n \n </li>\n<li>Know the type and strength of insulin you take.\n \n <span class=\"Bold\">Do not</span>change the type of insulin you take unless your healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin may need to change if you take different types of insulin.\n \n </li>\n<li>\n<span class=\"Bold\">Check your blood sugar levels.</span>Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels.\n \n </li>\n<li>\n<span class=\"Bold\">Do not reuse or share your needles or syringes with other people.</span>You may give other people a serious infection or get a serious infection from them.\n \n </li>\n<li>NovoLog Mix 70/30 is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs, or upper arms.</li>\n<li>\n<span class=\"Bold\">Change (rotate) your injection sites within the same area you choose with each dose</span>to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.\n \n <ul>\n<li>\n<span class=\"Bold\">Do not</span>use the exact same spot for each injection.\n \n </li>\n<li>\n<span class=\"Bold\">Do not</span>inject where skin has pits, is thickened, or has lumps.\n \n </li>\n<li>\n<span class=\"Bold\">Do not</span>inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.\n \n </li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"5\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What should I avoid while taking NovoLog Mix 70/30?</span>\n</p>\n<p>\n<span class=\"Bold\">While taking NovoLog Mix 70/30 do not:</span>\n</p>\n<ul>\n<li>Drive or operate heavy machinery, until you know how NovoLog Mix 70/30 affects you.</li>\n<li>Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"5\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of NovoLog Mix 70/30?</span>\n</p>\n<p>\n<span class=\"Bold\">NovoLog Mix 70/30 may cause serious side effects that can lead to death, including:</span>\n</p>\n<p>\n<span class=\"Bold\">Low blood sugar (hypoglycemia).</span>Signs and symptoms that may indicate low blood sugar include:\n \n </p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<ul>\n<li>dizziness or light-headedness</li>\n</ul>\n</td><td colspan=\"2\" valign=\"top\">\n<ul>\n<li>blurred vision</li>\n</ul>\n</td><td class=\"Rrule\" colspan=\"2\" valign=\"top\">\n<ul>\n<li>anxiety, irritability, or mood changes</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<ul>\n<li>sweating</li>\n</ul>\n</td><td colspan=\"2\" valign=\"top\">\n<ul>\n<li>slurred speech</li>\n</ul>\n</td><td class=\"Rrule\" colspan=\"2\" valign=\"top\">\n<ul>\n<li>hunger</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<ul>\n<li>confusion</li>\n</ul>\n</td><td colspan=\"2\" valign=\"top\">\n<ul>\n<li>shakiness</li>\n</ul>\n</td><td class=\"Rrule\" colspan=\"2\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<ul>\n<li>headache</li>\n</ul>\n</td><td colspan=\"2\" valign=\"top\">\n<ul>\n<li>fast heart beat</li>\n</ul>\n</td><td class=\"Rrule\" colspan=\"2\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"5\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Your insulin dose may need to change because of:</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" colspan=\"2\" valign=\"top\">\n<ul>\n<li>change in level of physical activity or exercise</li>\n</ul>\n</td><td colspan=\"2\" valign=\"top\">\n<ul>\n<li>increased stress</li>\n</ul>\n</td><td class=\"Rrule\" valign=\"top\">\n<ul>\n<li>change in diet</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" colspan=\"2\" valign=\"top\">\n<ul>\n<li>weight gain or loss</li>\n</ul>\n</td><td colspan=\"2\" valign=\"top\">\n<ul>\n<li>illness</li>\n</ul>\n</td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"5\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Other common side effects of NovoLog Mix 70/30 may include:</span>\n</p>\n<ul>\n<li>low potassium in your blood (hypokalemia), reactions at the injection site, itching, rash, serious allergic reactions (whole body reactions), skin thickening or pits at the injection site (lipodystrophy), weight gain, and swelling of your hands and feet.</li>\n</ul>\n<p>\n<span class=\"Bold\">Get emergency medical help if you have:</span>\n</p>\n<ul>\n<li>trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion.</li>\n</ul>\n<p>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.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"5\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of NovoLog Mix 70/30.</span>\n</p>\n<p>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.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"5\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in NovoLog Mix 70/30?</span>\n</p>\n<p>\n<span class=\"Bold\">Active Ingredient:</span>70% insulin aspart protamine and 30% insulin aspart.\n \n </p>\n<p>\n<span class=\"Bold\">Inactive Ingredients</span>: disodium hydrogen phosphate dihydrate, glycerol, metacresol, phenol, protamine sulfate, sodium chloride, zinc, and Water for Injection, USP. Hydrochloric acid or sodium hydroxide may be added to adjust pH.\n \n </p>\n<p>\n<span class=\"Bold\">Manufactured by:</span>Novo Nordisk Inc., Plainsboro, NJ 08536 U.S. License Number 1261\n \n </p>\n<p>For more information, go to www.novonordisk-us.com or call 1-800-727-6500.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Patient Information has been approved by the U.S. Food and Drug Administration

{ "type": "p", "children": [], "text": "This Patient Information has been approved by the U.S. Food and Drug Administration" }

Revised: 2/2023

{ "type": "p", "children": [], "text": "\nRevised: 2/2023\n" }

INSTRUCTIONS FOR USE

{ "type": "p", "children": [], "text": "\nINSTRUCTIONS FOR USE\n" }

NovoLog®Mix 70/30

{ "type": "p", "children": [], "text": "\nNovoLog®Mix 70/30\n" }

(insulin aspart protamine and insulin aspart)

{ "type": "p", "children": [], "text": "\n(insulin aspart protamine and insulin aspart)\n" }

injectable suspension, for subcutaneous use

{ "type": "p", "children": [], "text": "\ninjectable suspension, for subcutaneous use\n" }

10 mL multiple-dose vial (100 Units/mL, U-100)

{ "type": "p", "children": [], "text": "\n10 mL multiple-dose vial (100 Units/mL, U-100)\n" }

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.

{ "type": "p", "children": [], "text": "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:

{ "type": "p", "children": [], "text": "\nSupplies you will need to give your NovoLog Mix 70/30 injection:\n" }

{ "type": "ul", "children": [ "10 mL NovoLog Mix 70/30 vial", "insulin syringe and needle", "alcohol swabs" ], "text": "" }

Preparing your NovoLog Mix 70/30 dose:

{ "type": "p", "children": [], "text": "\nPreparing your NovoLog Mix 70/30 dose:\n" }

{ "type": "ul", "children": [ "Wash your hands with soap and water.", "Before you start to prepare your injection, check the NovoLog Mix 70/30 label to make sure that you are taking the right type of insulin. This is especially important if you use more than 1 type of insulin.", "NovoLog Mix 70/30 should look white and cloudy after mixing.\n \n Do notuse NovoLog Mix 70/30 if it looks clear or contains any lumps or particles.\n \n ", "NovoLog Mix 70/30 is easier to mix when it is at room temperature.", "After mixing NovoLog Mix 70/30, inject your dose right away. If you wait to inject your dose, the insulin will need to be mixed again.", "\nDo notuse NovoLog Mix 70/30 past the expiration date printed on the label.\n \n " ], "text": "" }

Step 1:If you are using a new vial, pull off the tamper-resistant cap (See Figure A).

{ "type": "p", "children": [], "text": "\nStep 1:If you are using a new vial, pull off the tamper-resistant cap (See Figure A).\n\n " }

Step 2:Wipe the rubber stopper with an alcohol swab (See Figure B).

{ "type": "p", "children": [], "text": "\nStep 2:Wipe the rubber stopper with an alcohol swab (See Figure B).\n\n " }

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.

{ "type": "p", "children": [], "text": "\nStep 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.\n \n Do not shake the vial.\n" }

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).

{ "type": "p", "children": [], "text": "\nStep 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).\n\n " }

Step 5:Push the needle through the rubber stopper of the NovoLog Mix 70/30 vial (See Figure E).

{ "type": "p", "children": [], "text": "\nStep 5:Push the needle through the rubber stopper of the NovoLog Mix 70/30 vial (See Figure E).\n\n " }

Step 6:Push the plunger all the way in. This puts air into the NovoLog Mix 70/30 vial (See Figure F).

{ "type": "p", "children": [], "text": "\nStep 6:Push the plunger all the way in. This puts air into the NovoLog Mix 70/30 vial (See Figure F).\n\n " }

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).

{ "type": "p", "children": [], "text": "\nStep 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).\n\n " }

{ "type": "ul", "children": [ "If there are air bubbles, tap the syringe gently a few times to let any air bubbles rise to the top (See Figure H)." ], "text": "" }

Step 8:Slowly push the plunger up until the black tip reaches the line for your NovoLog Mix 70/30 dose (See Figure I).

{ "type": "p", "children": [], "text": "\nStep 8:Slowly push the plunger up until the black tip reaches the line for your NovoLog Mix 70/30 dose (See Figure I).\n\n " }

Step 9:Check the syringe to make sure you have the right dose of NovoLog Mix 70/30.

{ "type": "p", "children": [], "text": "\nStep 9:Check the syringe to make sure you have the right dose of NovoLog Mix 70/30.\n\n " }

Step 10:Pull the syringe out of the vial’s rubber stopper (See Figure J).

{ "type": "p", "children": [], "text": "\nStep 10:Pull the syringe out of the vial’s rubber stopper (See Figure J).\n\n " }

Giving your injection:

{ "type": "p", "children": [], "text": "\nGiving your injection:\n" }

{ "type": "ul", "children": [ "Inject your NovoLog Mix 70/30 exactly as your healthcare provider has shown you. Your healthcare provider should tell you if you need to pinch the skin before injecting.", "NovoLog Mix 70/30 is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs, or upper arms.", "Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.\n \n Do notuse the same injection site for each injection. Do not inject where the skin has pits, thickened, or has lumps. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.\n \n " ], "text": "" }

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).

{ "type": "p", "children": [], "text": "\nStep 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).\n\n " }

Step 12:Insert the needle into your skin. Push down on the plunger to inject your dose (See Figure L). The needle should remain in the skin for at least 6 seconds to make sure you have injected all the insulin.

{ "type": "p", "children": [], "text": "\nStep 12:Insert the needle into your skin. Push down on the plunger to inject your dose (See Figure L). The needle should remain in the skin for at least 6 seconds to make sure you have injected all the insulin.\n\n " }

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).

{ "type": "p", "children": [], "text": "\nStep 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).\n\n " }

{ "type": "ul", "children": [ "If you see blood after you take the needle out of your skin, press the injection site lightly with a piece of gauze or an alcohol swab.\n \n Do notrub the area.\n \n " ], "text": "" }

After your injection:

{ "type": "p", "children": [], "text": "\nAfter your injection:\n" }

{ "type": "ul", "children": [ "\nDo notrecap the needle. Recapping the needle can lead to a needle stick injury.\n \n ", "Put the empty insulin vials, used needles and syringes in a FDA-cleared sharps disposal container right away after use.\n \n Do notthrow away (dispose of) loose needles and syringes in your household trash.\n \n ", "If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:\n \n \nmade of a heavy-duty plastic,\ncan be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,\nupright and stable during use,\nleak-resistant, and\nproperly labeled to warn of hazardous waste inside the container.\n\n", "When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at:\n \n http://www.fda.gov/safesharpsdisposal.\n \n \nDo notdispose of your used sharps disposal container in your household trash unless your community guidelines permit this.\n \n Do notrecycle your used sharps disposal container.\n \n \n" ], "text": "" }

How should I store NovoLog Mix 70/30?

{ "type": "p", "children": [], "text": "\nHow should I store NovoLog Mix 70/30?\n" }

{ "type": "ul", "children": [ "\nDo notfreeze NovoLog Mix 70/30.\n \n Do notuse NovoLog Mix 70/30 if it has been frozen.\n \n ", "Keep NovoLog Mix 70/30 away from heat or light.", "\nAll unopened vials:\n", "Store unopened NovoLog Mix 70/30 vials in the refrigerator at 36°F to 46°F (2°C to 8°C).", "Unopened vials may be used until the expiration date printed on the label, if they have been stored in the refrigerator.", "Unopened vials should be thrown away after 28 days, if they are stored at room temperature.", "\nAfter vials have been opened:\n", "Opened NovoLog Mix 70/30 vials can be stored in the refrigerator 36°F to 46°F (2°C to 8°C) or at room temperature below 86°F (30°C) for up to 28 days.", "Throw away all opened NovoLog Mix 70/30 vials after 28 days, even if they still have insulin left in them." ], "text": "" }

General information about the safe and effective use of NovoLog Mix 70/30

{ "type": "p", "children": [], "text": "\nGeneral information about the safe and effective use of NovoLog Mix 70/30\n" }

{ "type": "ul", "children": [ "Always use a new syringe and needle for each injection.", "Do not share syringes or needles.", "Keep NovoLog Mix 70/30 vials, syringes, and needles out of the reach of children." ], "text": "" }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration." }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Novo Nordisk Inc.

{ "type": "p", "children": [], "text": "Novo Nordisk Inc." }

800 Scudders Mill Road

{ "type": "p", "children": [], "text": "800 Scudders Mill Road" }

Plainsboro, New Jersey 08536

{ "type": "p", "children": [], "text": "Plainsboro, New Jersey 08536" }

1-800-727-6500

{ "type": "p", "children": [], "text": "1-800-727-6500" }

U.S. License Number 1261

{ "type": "p", "children": [], "text": "U.S. License Number 1261" }

Revised: 2/2023

{ "type": "p", "children": [], "text": "Revised: 2/2023" }

NovoLog ®is a registered trademark of Novo Nordisk A/S .

{ "type": "p", "children": [], "text": "\nNovoLog\n \n ®is a registered trademark of Novo Nordisk A/S\n \n .\n\n " }

PATENT Information: http://novonordisk-us.com/products/product-patents.html

{ "type": "p", "children": [], "text": "PATENT Information:\n \n http://novonordisk-us.com/products/product-patents.html\n" }

© 2023 Novo Nordisk

{ "type": "p", "children": [], "text": "© 2023 Novo Nordisk" }

For information about NovoLog Mix 70/30 contact:

{ "type": "p", "children": [], "text": "For information about NovoLog Mix 70/30 contact:" }

Novo Nordisk Inc.

{ "type": "p", "children": [], "text": "Novo Nordisk Inc." }

800 Scudders Mill Road

{ "type": "p", "children": [], "text": "800 Scudders Mill Road" }

Plainsboro, New Jersey 08536

{ "type": "p", "children": [], "text": "Plainsboro, New Jersey 08536" }

1-800-727-6500

{ "type": "p", "children": [], "text": "1-800-727-6500" }

www.novonordisk-us.com

{ "type": "p", "children": [], "text": "\nwww.novonordisk-us.com\n" }

INSTRUCTIONS FOR USE

{ "type": "p", "children": [], "text": "\nINSTRUCTIONS FOR USE\n" }

NovoLog ®Mix 70/30 FlexPen ®

{ "type": "p", "children": [], "text": "\nNovoLog\n \n ®Mix 70/30 FlexPen\n \n ®\n" }

(insulin aspart protamine and insulin aspart)

{ "type": "p", "children": [], "text": "\n(insulin aspart protamine and insulin aspart)\n" }

injectable suspension, for subcutaneous use

{ "type": "p", "children": [], "text": "\ninjectable suspension, for subcutaneous use\n" }

FlexPen ®

{ "type": "p", "children": [], "text": "\nFlexPen\n \n ®\n" }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "\nDo 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.\n\n " }

NovoLog Mix 70/30 FlexPen is a disposable, single-patient-use 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.

{ "type": "p", "children": [], "text": "NovoLog Mix 70/30 FlexPen is a disposable, single-patient-use 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." }

People who are blind or have vision problems should not use NovoLog Mix 70/30 FlexPen without help from a person trained to use NovoLog Mix 70/30 FlexPen.

{ "type": "p", "children": [], "text": "\nPeople who are blind or have vision problems should not use NovoLog Mix 70/30 FlexPen without help from a person trained to use NovoLog Mix 70/30 FlexPen.\n\n " }

Getting ready

{ "type": "p", "children": [], "text": "\nGetting ready\n" }

Make sure you have the following items:

{ "type": "p", "children": [], "text": "Make sure you have the following items:" }

{ "type": "ul", "children": [ "NovoLog Mix 70/30 FlexPen", "New NovoFine, NovoFine Plus or NovoTwist needle", "Alcohol swabs" ], "text": "" }

Preparing your NovoLog Mix 70/30 FlexPen

{ "type": "p", "children": [], "text": "\nPreparing your NovoLog Mix 70/30 FlexPen\n" }

{ "type": "ul", "children": [ "Wash your hands with soap and water.", "Before you start to prepare your injection, check the label to make sure that you are taking the right type of insulin. This is especially important if you take more than 1 type of insulin. NovoLog Mix 70/30 should look cloudy after mixing." ], "text": "" }

Before your first injection with a new NovoLog Mix 70/30 FlexPen you must mix the insulin:

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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).

{ "type": "p", "children": [], "text": "Pull off the pen cap (see diagram A)." }

B. Roll the pen between your palms 10 times - it is important that the pen is kept horizontal (see diagram B).

{ "type": "p", "children": [], "text": "B. Roll the pen between your palms 10 times - it is important that the pen is kept horizontal (see diagram B)." }

C. Then gently move the pen up and down ten times between position 1and 2as shown, so the glass ball moves from one end of the cartridge to the other (see diagram C).

{ "type": "p", "children": [], "text": "C. Then gently move the pen up and down ten times between position\n \n 1and\n \n 2as shown, so the glass ball moves from one end of the cartridge to the other (see diagram C).\n\n " }

 Repeat rolling and moving the pen until the liquid appears white and cloudy. Do not use the pen if the liquid appears discolored or contains particles.

{ "type": "p", "children": [], "text": " Repeat rolling and moving the pen until the liquid appears white and cloudy. Do not use the pen if the liquid appears discolored or contains particles." }

For every following injectionmove the pen up and down between positions 1 and 2 at least ten times until the liquid appears white and cloudy.

{ "type": "p", "children": [], "text": "\nFor every following injectionmove the pen up and down between positions 1 and 2 at least ten times until the liquid appears white and cloudy.\n\n " }

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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "Wipe the rubber stopper with an alcohol swab." }

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.

{ "type": "p", "children": [], "text": "\nBefore 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.\n\n " }

Attaching the needle

{ "type": "p", "children": [], "text": "\nAttaching the needle\n" }

D. Remove the protective tab from a disposable needle.

{ "type": "p", "children": [], "text": "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).

{ "type": "p", "children": [], "text": "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. 

{ "type": "p", "children": [], "text": "Never place a disposable needle on your NovoLog Mix 70/30 FlexPen until you are ready to take your injection. " }

E. Pull off the big outer needle cap (see diagram E).

{ "type": "p", "children": [], "text": "E. Pull off the big outer needle cap (see diagram E)." }

F. Pull off the inner needle cap and throw it away (dispose of it) (see diagram F).

{ "type": "p", "children": [], "text": "F. Pull off the inner needle cap and throw it away (dispose of it) (see diagram F)." }

{ "type": "ul", "children": [ "\n\nAlways use a new needle for each injection to make sure the needle is free of germs (sterile) and to prevent blocked needles. Do not reuse or share your needles or syringes with other people. You may give other people a serious infection, or get a serious infection from them.\n \n " ], "text": "" }

Be careful not to bend or damage the needle before use.

{ "type": "p", "children": [], "text": "\nBe careful not to bend or damage the needle before use.\n\n " }

To reduce the risk of a needle stick, never put the inner needle cap back on the needle.

{ "type": "p", "children": [], "text": "\nTo reduce the risk of a needle stick,\n \n never put the inner needle cap back on the needle.\n" }

Giving the airshot before each injection

{ "type": "p", "children": [], "text": "\nGiving the airshot before each injection\n" }

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:

{ "type": "p", "children": [], "text": "Before each injection small amounts of air may collect in the cartridge during normal use.\n \n To avoid injecting air and to make sure you take the right dose of insulin:\n\n " }

G. Turn the dose selector to select 2 units (see diagram G).

{ "type": "p", "children": [], "text": "G. Turn the dose selector to select 2 units (see diagram G)." }

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).

{ "type": "p", "children": [], "text": "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)." }

I. Keep the needle pointing upwards, press the push-button all the way in (see diagram I). The dose selector returns to 0.

{ "type": "p", "children": [], "text": "I. Keep the needle pointing upwards, press the push-button all the way in (see diagram I). The dose selector returns to 0." }

A drop of insulin should appear at the needle tip. If not, change the needle and repeat the procedure no more than 6 times.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "A small air bubble may remain at the needle tip, but it will not be injected." }

Selecting your dose

{ "type": "p", "children": [], "text": "\nSelecting your dose\n" }

Check and make sure that the dose selector is set at 0.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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 because you may get an incorrect dose.

{ "type": "p", "children": [], "text": "You will hear a click for every single unit dialed. Do not set the dose by counting the number of clicks you hear because you may get an incorrect dose." }

Do not use the cartridge scale printed on the cartridge to measure your dose of insulin.

{ "type": "p", "children": [], "text": "\nDo not use the cartridge scale printed on the cartridge to measure your dose of insulin.\n\n " }

Giving the injection

{ "type": "p", "children": [], "text": "\nGiving the injection\n" }

{ "type": "ul", "children": [ "Do the injection exactly as shown to you by your healthcare provider. Your healthcare provider should tell you if you need to pinch the skin before injecting. Wipe the skin with an alcohol swab and let the area dry.", "NovoLog Mix 70/30 can be injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs (thighs), or upper arms.", "Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.\n \n Do notuse the same injection site for each injection. Do not inject where the skin has pits, is thickened, or has lumps. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.\n \n " ], "text": "" }

K. Insert the needle into your skin.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "Turning the dose selector will not inject insulin." }

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.

{ "type": "p", "children": [], "text": "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." }

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.

{ "type": "p", "children": [], "text": "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.\n \n Do not rub the area.\n" }

After the injection

{ "type": "p", "children": [], "text": "\nAfter the injection\n" }

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.

{ "type": "p", "children": [], "text": "\nDo 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.\n\n " }

{ "type": "ul", "children": [ "Put your used needles in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles in your household trash.", "If you do not have a FDA-cleared sharps disposal container, carefully slip the needle into the outer needle cap and throw it away in a household container that is:\n \n \nmade of a heavy-duty plastic,\ncan be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,\nupright and stable during use,\nleak-resistant, and\nproperly labeled to warn of hazardous waste inside the container\n\n", "When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at:\n \n http://www.fda.gov/safesharpsdisposal.\n \n ", "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.", "When there is not enough medicine left in your NovoLog Mix 70/30 FlexPen for your prescribed dose, the NovoLog Mix 70/30 FlexPen may be thrown away in your household trash after you have removed the needle. The NovoLog Mix 70/30 FlexPen prevents the cartridge from being completely emptied. It is designed to deliver 300 units." ], "text": "" }

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.

{ "type": "p", "children": [], "text": "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." }

How should I store NovoLog Mix 70/30 FlexPen?

{ "type": "p", "children": [], "text": "\nHow should I store NovoLog Mix 70/30 FlexPen?\n" }

{ "type": "ul", "children": [ "\nDo notfreeze NovoLog Mix 70/30.\n \n Do notuse NovoLog Mix 70/30 if it has been frozen.\n \n ", "Keep NovoLog Mix 70/30 away from heat or light.", "Store the NovoLog Mix 70/30 FlexPen without the needle attached.", "\nUnused NovoLog Mix 70/30 FlexPen:\n\nStore unused NovoLog Mix 70/30 FlexPen in the refrigerator at 36°F to 46°F (2°C to 8°C).\nUnused NovoLog Mix 70/30 FlexPen may be used until the expiration date printed on the label, if kept in the refrigerator.\nUnused NovoLog Mix 70/30 FlexPen should be thrown away after 14 days, if it is stored at room temperature.\n\n", "\nIn-Use NovoLog Mix 70/30 FlexPen:\n\nStore the FlexPen you are currently using at room temperature below 86°F (30°C) for up to 14 days.\nThe NovoLog Mix 70/30 FlexPen you are using should be thrown away after 14 days, even if it still has insulin left in it.\n\n" ], "text": "" }

Maintenance

{ "type": "p", "children": [], "text": "\nMaintenance\n" }

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.

{ "type": "p", "children": [], "text": "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." }

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.

{ "type": "p", "children": [], "text": "\nRemove 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.\n\n " }

Be careful when handling used needles to avoid needle sticks and transfer of infectious diseases.

{ "type": "p", "children": [], "text": "\nBe careful when handling used needles to avoid needle sticks and transfer of infectious diseases.\n\n " }

Keep your NovoLog Mix 70/30 FlexPen and needles out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep your NovoLog Mix 70/30 FlexPen and needles out of the reach of children.\n\n " }

Use NovoLog Mix 70/30 FlexPen as directed to treat your diabetes.

{ "type": "p", "children": [], "text": "\nUse NovoLog Mix 70/30 FlexPen as directed to treat your diabetes.\n\n " }

Do notshare 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.

{ "type": "p", "children": [], "text": "\nDo notshare 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.\n\n " }

Always use a new needle for each injection.

{ "type": "p", "children": [], "text": "\nAlways use a new needle for each injection.\n\n " }

Novo Nordisk is not responsible for harm due to using this insulin pen with products not recommended by Novo Nordisk.

{ "type": "p", "children": [], "text": "\nNovo Nordisk is not responsible for harm due to using this insulin pen with products not recommended by Novo Nordisk.\n\n " }

As a precautionary measure, always carry a spare insulin delivery device in case your NovoLog Mix 70/30 FlexPen is lost or damaged.

{ "type": "p", "children": [], "text": "\nAs a precautionary measure, always carry a spare insulin delivery device in case your NovoLog Mix 70/30 FlexPen is lost or damaged.\n\n " }

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.

{ "type": "p", "children": [], "text": "\nRemember 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.\n\n " }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration." }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Novo Nordisk Inc.

{ "type": "p", "children": [], "text": "Novo Nordisk Inc." }

800 Scudders Mill Road

{ "type": "p", "children": [], "text": "800 Scudders Mill Road" }

Plainsboro, New Jersey 08536

{ "type": "p", "children": [], "text": "Plainsboro, New Jersey 08536" }

1-800-727-6500

{ "type": "p", "children": [], "text": "1-800-727-6500" }

U.S. License Number 1261

{ "type": "p", "children": [], "text": "U.S. License Number 1261" }

Revised: 2/2023

{ "type": "p", "children": [], "text": "\nRevised: 2/2023\n" }

DRUG: NovoLog Mix 70/30

{ "type": "p", "children": [], "text": "DRUG: NovoLog Mix 70/30" }

GENERIC: insulin aspart

{ "type": "p", "children": [], "text": "GENERIC: insulin aspart" }

DOSAGE: INJECTION, SUSPENSION

{ "type": "p", "children": [], "text": "DOSAGE: INJECTION, SUSPENSION" }

ADMINSTRATION: SUBCUTANEOUS

{ "type": "p", "children": [], "text": "ADMINSTRATION: SUBCUTANEOUS" }

NDC: 70518-2119-0

{ "type": "p", "children": [], "text": "NDC: 70518-2119-0" }

PACKAGING: 3 mL in 1 SYRINGE, PLASTIC

{ "type": "p", "children": [], "text": "PACKAGING: 3 mL in 1 SYRINGE, PLASTIC" }

OUTER PACKAGING: 5 in 1 CARTON

{ "type": "p", "children": [], "text": "OUTER PACKAGING: 5 in 1 CARTON" }

ACTIVE INGREDIENT(S):

{ "type": "p", "children": [], "text": "ACTIVE INGREDIENT(S):" }

{ "type": "ul", "children": [ "INSULIN ASPART 100[iU] in 1mL" ], "text": "" }

INACTIVE INGREDIENT(S):

{ "type": "p", "children": [], "text": "INACTIVE INGREDIENT(S):" }

{ "type": "ul", "children": [ "SODIUM PHOSPHATE, DIBASIC, DIHYDRATE", "GLYCERIN", "HYDROCHLORIC ACID", "METACRESOL", "PHENOL", "PROTAMINE SULFATE", "SODIUM CHLORIDE", "SODIUM HYDROXIDE", "ZINC" ], "text": "" }

Limitations of Use:

TOUJEO is not recommended for the treatment of diabetic ketoacidosis.

Recommended Starting Dosage in Patients with Type 1 Diabetes

Recommended Starting Dosage in Patients with Type 2 Diabetes

Dosage adjustments are recommended to lower the risk of hypoglycemia when switching patients to TOUJEO from another insulin therapy [see Warnings and Precautions (5.3)].

Injection: 300 units/mL (U-300) of insulin glargine in a clear, colorless, solution available as:

{ "type": "p", "children": [], "text": "Injection: 300 units/mL (U-300) of insulin glargine in a clear, colorless, solution available as:" }

{ "type": "ul", "children": [ "1.5 mL SoloStar single-patient-use prefilled pen (450 units per 1.5 mL pen)", "3 mL Max SoloStar single-patient-use prefilled pen (900 units per 3 mL pen)" ], "text": "" }

TOUJEO is contraindicated:

{ "type": "p", "children": [], "text": "TOUJEO is contraindicated:" }

{ "type": "ul", "children": [ "During episodes of hypoglycemia [see Warnings and Precautions (5.3)].", "In patients with hypersensitivity to insulin glargine or any excipients in TOUJEO [see Warnings and Precautions (5.5)]." ], "text": "" }

TOUJEO SoloStar or TOUJEO Max SoloStar single-patient-use prefilled pens must never be shared between patients, even if the needle is changed. Pen sharing poses a risk for transmission of blood-borne pathogens.

Changes in Insulin Regimen Including Changes to Administration Site

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 unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions (6)].

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 oral antidiabetic products may be needed.

Changing to TOUJEO from other Insulin Therapies

On a unit-to-unit basis, TOUJEO has a lower glucose lowering effect than LANTUS [see Clinical Pharmacology (12.2)]. In clinical trials, patients who changed to TOUJEO from other basal insulins experienced higher average fasting plasma glucose levels in the first weeks of therapy compared to patients who were changed to LANTUS. Higher doses of TOUJEO were required to achieve similar levels of glucose control compared to LANTUS in clinical trials [see Clinical Studies (14.1)].

The onset of action of TOUJEO develops over 6 hours following an injection. In type 1 diabetes patients treated with IV insulin, consider the longer onset of action of TOUJEO before stopping IV insulin. The full glucose lowering effect may not be apparent for at least 5 days [see Dosage and Administration (2.2) and Clinical Pharmacology (12.2)].

To minimize the risk of hyperglycemia when initiating TOUJEO monitor glucose daily, titrate TOUJEO as described in this prescribing information, and adjust coadministered glucose-lowering therapies per standard of care [see Dosage and Administration (2.2, 2.3)].

Hypoglycemia is the most common adverse reaction associated with insulin, including TOUJEO. Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place the patient 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 patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, in patients using drugs that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7)], or who experience recurrent hypoglycemia.

The long-acting effect of TOUJEO may delay recovery from hypoglycemia compared to shorter-acting insulins.

Risk Factors for Hypoglycemia

The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation. As with all insulins, the glucose lowering effect time course of TOUJEO may vary in different patients or at different times in the same patient 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 concomitant drugs [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. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. To minimize the risk of hypoglycemia, do not administer TOUJEO intravenously, intramuscularly or in an insulin pump, or dilute or mix TOUJEO with any other insulin products or solutions.

Accidental mix-ups between insulin products have been reported. To avoid medication errors between TOUJEO and other insulins, instruct patients to always check the insulin label before each injection.

To avoid dosing errors and potential overdose, never use a syringe to remove TOUJEO from the TOUJEO SoloStar or TOUJEO Max SoloStar prefilled pen into a syringe [see Dosage and Administration (2.4) and Warnings and Precautions (5.3)].

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including TOUJEO. If hypersensitivity reactions occur, discontinue TOUJEO; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6)]. TOUJEO is contraindicated in patients who have had hypersensitivity reactions to insulin glargine or any of the excipients in TOUJEO.

All insulins, including TOUJEO, 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 concentrations).

Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including TOUJEO, 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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates actually observed in clinical practice.

The data in Table 1 reflect the exposure of 304 patients with type 1 diabetes to TOUJEO with mean exposure duration of 23 weeks. The type 1 diabetes population had the following characteristics: Mean age was 46 years and mean duration of diabetes was 21 years. Fifty-five percent were male, 86% were White, 5% were Black or African American, and 5% were Hispanic or Latino. At baseline, the mean eGFR was 82 mL/min/1.73 m2 and 35% of patients had eGFR ≥90 mL/min/1.73 m2. The mean body mass index (BMI) was 28 kg/m2. HbA1c at baseline was greater than or equal to 8% in 58% of patients.

The data in Table 2 reflect the exposure of 1242 patients with type 2 diabetes to TOUJEO with mean exposure duration of 25 weeks. The type 2 diabetes population had the following characteristics: Mean age was 59 years and mean duration of diabetes was 13 years. Fifty-three percent were male, 88% were White, 7% were Black or African American, and 17% were Hispanic or Latino. At baseline, mean eGFR was 79 mL/min/1.73 m2 and 27% of patients had an eGFR ≥90 mL/min/1.73 m2. The mean BMI was 35 kg/m2. HbA1c at baseline was greater than or equal to 8% in 66% of patients.

TOUJEO was studied in 233 pediatric patients (6–17 years of age) with type 1 diabetes for a mean duration of 26 weeks [see Clinical Studies (14.1)].

Common adverse reactions (occurring ≥5%) in TOUJEO-treated subjects during clinical trials in adult patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in Table 1 and Table 2, respectively. Common adverse reactions for TOUJEO-treated pediatric subjects with type 1 diabetes mellitus were similar to the adverse reactions listed in Table 1. Hypoglycemia is discussed in a dedicated subsection below.

<div class="scrollingtable"><table width="65%"> <caption> <span>Table 1: Adverse Reactions Occurring ≥5% in Two Pooled Clinical Trials of 26 Weeks and 16 Weeks Duration in Adults with Type 1 Diabetes</span> </caption> <col align="left" valign="middle" width="45%"/> <col align="center" valign="middle" width="55%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">TOUJEO + Mealtime Insulin<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a>, %<br/>(n=304)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>"mealtime insulin" refers to insulin glulisine, insulin lispro, or insulin aspart.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Nasopharyngitis</td><td align="center" class="Rrule">12.8</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Upper respiratory tract infection</td><td align="center" class="Rrule">9.5</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="65%"> <caption> <span>Table 2: Adverse Reactions Occurring ≥5% in Three Pooled Clinical Trials of 26 Weeks Duration in Adults with Type 2 Diabetes</span> </caption> <col align="left" valign="middle" width="45%"/> <col align="center" valign="middle" width="55%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">TOUJEO<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a>, %<br/>(n=1242)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>one of the trials in type 2 diabetes included mealtime insulin.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Nasopharyngitis</td><td align="center" class="Rrule">7.1</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Upper respiratory tract infection</td><td align="center" class="Rrule">5.7</td> </tr> </tbody> </table></div>

Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients treated with TOUJEO. 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 TOUJEO 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.

In the TOUJEO adult program, severe hypoglycemia was defined as an event requiring assistance of another person to administer a resuscitative action. In the pediatric program, severe hypoglycemia was defined as an event with semiconsciousness, unconsciousness, coma and/or convulsions in a patient who had altered mental status and could not assist in his own care, and who may have required glucagon or intravenous glucose.

The incidence of severe hypoglycemia in adult patients with type 1 diabetes receiving TOUJEO as part of a multiple daily injection regimen was 6.6% at 26 weeks. The incidence of hypoglycemia with a glucose level less than 54 mg/dL with or without symptoms was 77.7% at 26 weeks.

The incidence of severe hypoglycemia in pediatric patients with type 1 diabetes receiving TOUJEO as part of a multiple daily injection regimen was 6% at 26 weeks and the incidence of hypoglycemia accompanied by a self-monitored or plasma glucose value less than 54 mg/dL regardless of symptoms was 80.3%.

The incidence of severe hypoglycemia in adult patients with type 2 diabetes was 5% at 26 weeks in patients receiving TOUJEO as part of a multiple daily injection regimen, and 1.0% and 0.9% respectively at 26 weeks in the two studies where patients received TOUJEO as part of a basal-insulin only regimen. The incidence of hypoglycemia accompanied by a self-monitored or plasma glucose value less than 54 mg/dL regardless of symptoms in patients with type 2 diabetes receiving TOUJEO ranged from 9% to 44.6% at 26 weeks and the highest risk was again seen in patients receiving TOUJEO as part of a multiple daily injection regimen.

Insulin Initiation and Intensification of Glucose Control

Intensification or rapid improvement in glucose control has been associated with a 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.

Peripheral Edema

Insulin, including TOUJEO, may cause sodium retention and edema, particularly if previously poor metabolic control was improved by intensified insulin therapy.

Lipodystrophy

Long-term use of insulin, including TOUJEO, can cause lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients and may affect insulin absorption [see Dosage and Administration (2.1)].

Weight Gain

Weight gain has occurred with insulins, including TOUJEO and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.

Hypersensitivity Reactions

Patients taking TOUJEO experienced erythema, local edema, and pruritus at the site of injection. These conditions were usually self-limiting.

Severe cases of generalized allergy (anaphylaxis) have been reported.

As with all therapeutic proteins, there is potential for immunogenicity.

In a 6-month study of type 1 diabetes patients, 79% of patients who received TOUJEO once daily were positive for anti-insulin antibodies (AIA) at least once during the study, including 62% that were positive at baseline and 44% of patients who developed antidrug antibody (i.e., anti-insulin glargine antibody [ADA]) during the study. Eighty percent of the AIA-positive patients on TOUJEO with antibody test at baseline remained AIA positive at month 6.

In two 6-month studies in type 2 diabetes patients, 25% of patients who received TOUJEO once daily were positive for AIA at least once during the study, including 42% who were positive at baseline and 20% of patients who developed ADA during the study. Ninety percent of the AIA-positive patients on TOUJEO with antibody test at baseline, remained AIA positive at month 6.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to TOUJEO with the incidence of antibodies in other studies or to other products may be misleading.

The following additional adverse reactions have been identified during postapproval use of TOUJEO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.

Table 3 includes clinically significant drug interactions with TOUJEO.

{ "type": "p", "children": [], "text": "Table 3 includes clinically significant drug interactions with TOUJEO." }

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 3: Clinically Significant Drug Interactions with TOUJEO</span> </caption> <col align="left" valign="middle" width="20%"/> <col align="left" valign="middle" width="80%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Drugs That May Increase the Risk of Hypoglycemia</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Drugs:</span></td><td align="left" class="Rrule">Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Intervention:</span></td><td align="left" class="Rrule">Dosage reductions and increased frequency of glucose monitoring may be required when TOUJEO is coadministered with these drugs.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Drugs That May Decrease the Blood Glucose Lowering Effect of TOUJEO</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Drugs:</span></td><td align="left" class="Rrule">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.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Intervention:</span></td><td align="left" class="Rrule">Dosage increases and increased frequency of glucose monitoring may be required when TOUJEO is coadministered with these drugs.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of TOUJEO</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Drugs:</span></td><td align="left" class="Rrule">Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Intervention:</span></td><td align="left" class="Rrule">Dosage adjustment and increased frequency of glucose monitoring may be required when TOUJEO is coadministered with these drugs.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Drugs That May Blunt Signs and Symptoms of Hypoglycemia </span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Drugs:</span></td><td align="left" class="Rrule">Beta-blockers, clonidine, guanethidine, and reserpine.</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"><span class="Italics">Intervention:</span></td><td align="left" class="Rrule">Increased frequency of glucose monitoring may be required when TOUJEO is coadministered with these drugs.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"75%\">\n<caption>\n<span>Table 3: Clinically Significant Drug Interactions with TOUJEO</span>\n</caption>\n<col align=\"left\" valign=\"middle\" width=\"20%\"/>\n<col align=\"left\" valign=\"middle\" width=\"80%\"/>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Drugs That May Increase the Risk of Hypoglycemia</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\"><span class=\"Italics\">Drugs:</span></td><td align=\"left\" class=\"Rrule\">Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Rrule\">Dosage reductions and increased frequency of glucose monitoring may be required when TOUJEO is coadministered with these drugs.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Drugs That May Decrease the Blood Glucose Lowering Effect of TOUJEO</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\"><span class=\"Italics\">Drugs:</span></td><td align=\"left\" class=\"Rrule\">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.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Rrule\">Dosage increases and increased frequency of glucose monitoring may be required when TOUJEO is coadministered with these drugs.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of TOUJEO</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\"><span class=\"Italics\">Drugs:</span></td><td align=\"left\" class=\"Rrule\">Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Rrule\">Dosage adjustment and increased frequency of glucose monitoring may be required when TOUJEO is coadministered with these drugs.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Drugs That May Blunt Signs and Symptoms of Hypoglycemia </span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\"><span class=\"Italics\">Drugs:</span></td><td align=\"left\" class=\"Rrule\">Beta-blockers, clonidine, guanethidine, and reserpine.</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Rrule\">Increased frequency of glucose monitoring may be required when TOUJEO is coadministered with these drugs.</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Published studies with use of insulin glargine during pregnancy have not reported a clear association with insulin glargine and adverse developmental outcomes (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations).

Rats and rabbits were exposed to insulin glargine in animal reproduction studies during organogenesis, respectively 50 times and 10 times the human subcutaneous dose of 0.2 unit/kg/day. Overall, the effects of insulin glargine did not generally differ from those observed with regular human insulin (see Data).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated background risk of major birth defects is 6% to 10% in women with pregestational diabetes with a peri-conceptional HbA1c >7 and has been reported to be as high as 20% to 25% in women with a peri-conceptional HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/fetal Risk

Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. 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, stillbirth, and macrosomia-related morbidity.

Data

Human Data

Published data do not report a clear association with insulin glargine and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin glargine is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations including small sample size and some lacking comparator groups.

Animal Data

Subcutaneous reproduction and teratology studies have been performed with insulin glargine and regular human insulin in rats and Himalayan rabbits. Insulin glargine was given to female rats before mating, during mating, and throughout pregnancy at doses up to 0.36 mg/kg/day, which is approximately 50 times the recommended human subcutaneous starting dosage of 0.2 Units/kg/day (0.007 mg/kg/day). In rabbits, doses of 0.072 mg/kg/day, which is approximately 10 times the recommended human subcutaneous starting dosage of 0.2 Units/kg/day (0.007 mg/kg/day), were administered during organogenesis. The effects of insulin glargine did not generally differ from those observed with regular human insulin in rats or rabbits. However, in rabbits, five fetuses from two litters of the high-dose group exhibited dilation of the cerebral ventricles. Fertility and early embryonic development appeared normal.

Risk Summary

There are either no or only limited data on the presence of insulin glargine in human milk, the effects on breastfed infant, or the effects on milk production. Endogenous insulin is present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TOUJEO, and any potential adverse effects on the breastfed child from TOUJEO or from the underlying maternal condition.

The safety and effectiveness of TOUJEO to improve glycemic control in pediatric patients 6 years of age and older with diabetes mellitus have been established.

The use of TOUJEO for this indication is supported by evidence from an adequate and well-controlled study in 463 pediatric patients 6 to 17 years of age with type 1 diabetes mellitus [see Clinical Studies (14.2)] and from studies in adults with diabetes mellitus [see Clinical Pharmacology (12.3), Clinical Studies (14.3)].

The safety and effectiveness of TOUJEO have not been established in pediatric patients less than 6 years of age.

In controlled clinical studies, 30 of 304 (9.8%) TOUJEO-treated patients with type 1 diabetes and 327 of 1242 (26.3%) TOUJEO-treated patients with type 2 diabetes were ≥65 years of age, among them 2.0% of the patients with type 1 and 3.0% of the patients with type 2 diabetes were ≥75 years of age. No overall differences in safety or effectiveness of TOUJEO have been observed between patients 65 years of age and older and younger adult patients.

Nevertheless, caution should be exercised when TOUJEO is administered to geriatric patients. In geriatric patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia [see Warnings and Precautions (5.3), Adverse Reactions (6), and Clinical Studies (14)].

The effect of kidney impairment on the pharmacokinetics of TOUJEO has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with kidney failure. Frequent glucose monitoring and dose adjustment may be necessary for TOUJEO in patients with kidney impairment [see Warnings and Precautions (5.3)].

The effect of hepatic impairment on the pharmacokinetics of TOUJEO has not been studied. Frequent glucose monitoring and dose adjustment may be necessary for TOUJEO in patients with hepatic impairment [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 can be treated with oral glucose. Lowering the insulin dosage, and adjustments in meal patterns, or physical activity level may be needed. More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with glucagon for emergency use 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.

{ "type": "p", "children": [], "text": "Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.6)]. Mild episodes of hypoglycemia can be treated with oral glucose. Lowering the insulin dosage, and adjustments in meal patterns, or physical activity level may be needed. More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with glucagon for emergency use 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." }

Insulin glargine is a long-acting human insulin analog produced by recombinant DNA technology utilizing a nonpathogenic laboratory strain of Escherichia coli (K12) as the production organism. Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines remain at the C-terminus of the B-chain. Insulin glargine has a molecular weight of 6063 Da.

{ "type": "p", "children": [], "text": "Insulin glargine is a long-acting human insulin analog produced by recombinant DNA technology utilizing a nonpathogenic laboratory strain of Escherichia coli (K12) as the production organism. Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines remain at the C-terminus of the B-chain. Insulin glargine has a molecular weight of 6063 Da." }

TOUJEO (insulin glargine) injection is a sterile, clear and colorless solution for subcutaneous injection. Each mL of TOUJEO contains 300 units of insulin glargine dissolved in a clear aqueous fluid.

{ "type": "p", "children": [], "text": "TOUJEO (insulin glargine) injection is a sterile, clear and colorless solution for subcutaneous injection. Each mL of TOUJEO contains 300 units of insulin glargine dissolved in a clear aqueous fluid." }

The 1.5 mL TOUJEO SoloStar prefilled pen presentation contains the following inactive ingredients per mL: glycerin (20 mg), metacresol (2.7 mg), zinc (90 mcg), and Water for Injection, USP.

{ "type": "p", "children": [], "text": "The 1.5 mL TOUJEO SoloStar prefilled pen presentation contains the following inactive ingredients per mL: glycerin (20 mg), metacresol (2.7 mg), zinc (90 mcg), and Water for Injection, USP." }

The 3 mL TOUJEO Max SoloStar prefilled pen presentation contains the following inactive ingredients per mL: glycerin (20 mg), metacresol (2.7 mg), zinc (90 mcg), and Water for Injection, USP.

{ "type": "p", "children": [], "text": "The 3 mL TOUJEO Max SoloStar prefilled pen presentation contains the following inactive ingredients per mL: glycerin (20 mg), metacresol (2.7 mg), zinc (90 mcg), and Water for Injection, USP." }

The pH is adjusted by addition of aqueous solutions of hydrochloric acid and sodium hydroxide. TOUJEO has a pH of approximately 4.

{ "type": "p", "children": [], "text": "The pH is adjusted by addition of aqueous solutions of hydrochloric acid and sodium hydroxide. TOUJEO has a pH of approximately 4." }

The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogs 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.

Onset of Action

The pharmacodynamic profiles for TOUJEO given subcutaneously as a single dose of 0.4, 0.6, or 0.9 U/kg in a euglycemic clamp study in patients with type 1 diabetes showed that on average, the onset of action develops over 6 hours post dose for all three single doses of TOUJEO.

Single-Dose Pharmacodynamics

The pharmacodynamics for single 0.4, 0.6, and 0.9 U/kg doses of TOUJEO in 24 patients with type 1 diabetes mellitus was evaluated in a euglycemic clamp study. On a unit-to-unit basis, TOUJEO had a lower maximum (GIRmax) and 24-hour glucose lowering effect (GIR-AUC0–24) compared to LANTUS. The overall glucose lowering effect of TOUJEO 0.4 U/kg was 12% of the glucose lowering effect of an equivalent dose of LANTUS. Glucose lowering at least 30% of the effect of a single 0.4 U/kg dose of LANTUS was not observed until the single dose of TOUJEO exceeded 0.6 U/kg.

Multiple Once-Daily Dose Pharmacodynamics

The pharmacodynamics of TOUJEO after 8 days of daily injection was evaluated in 30 patients with type 1 diabetes. At steady state, the 24-hour glucose lowering effect (GIR-AUC0–24) of TOUJEO 0.4 U/kg was approximately 27% lower with a different distribution profile than that of an equivalent dose of LANTUS [see Dosage and Administration (2), Warnings and Precautions (5.2), and Clinical Pharmacology (12.3)]. The glucose lowering effect of a TOUJEO dose increased with each daily administration.

The pharmacodynamic profile for TOUJEO given subcutaneously as multiple once-daily subcutaneous injections of 0.4 U/kg in a euglycemic clamp study in patients with type 1 diabetes is shown in Figure 1.

Figure 1: Glucose Infusion Rate in Patients with Type 1 Diabetes in Multiple-Dose Administration of TOUJEO

Glucose infusion rate: determined as amount of glucose infused to maintain constant plasma glucose levels.

Absorption

The pharmacokinetic profiles for single 0.4, 0.6, and 0.9 U/kg doses of TOUJEO in 24 patients with type 1 diabetes mellitus was evaluated in a euglycemic clamp study. The median time to maximum serum insulin concentration was 12 (8–14), 12 (12–18), and 16 (12–20) hours, respectively. Mean serum insulin concentrations declined to the lower limit of quantitation of 5.02 µU/mL by 16, 28, and beyond 36 hours, respectively.

Steady-state insulin concentrations are reached by at least 5 days of once-daily subcutaneous administration of 0.4 U/kg to 0.6 U/kg doses of TOUJEO over 8 days in patients with type 1 diabetes mellitus.

After subcutaneous injection of TOUJEO, the intra-subject variability, defined as the coefficient of variation for the insulin exposure during 24 hours, was 21.0% at steady state.

Elimination

After subcutaneous injection of TOUJEO in diabetic patients, insulin glargine is metabolized at the carboxyl terminus of the B-chain with formation of two active metabolites M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin). The in vitro activity of M1 and M2 were similar to that of human insulin.

Specific Populations

Pediatrics

Population pharmacokinetic analysis was conducted for TOUJEO based on concentration data of its main metabolite M1 using data from 75 pediatric patients (6 to <18 years of age) with type 1 diabetes. The findings with regard to the effect of body weight on systemic exposure of M1 are generally consistent with findings in adults.

Elderly, Race, Sex, and Obesity

Effect of age ≥65, race, and sex on the pharmacokinetics of TOUJEO has not been evaluated. When weight is taken into account as a covariate on clearance, BMI is not an additional covariate.

In mice and rats, standard two-year carcinogenicity studies with insulin glargine were performed at doses up to 0.455 mg/kg, which was for the rat approximately 65 times the recommended human subcutaneous starting dosage of 0.2 Units/kg/day (0.007 mg/kg/day). The findings in female mice were not conclusive due to excessive mortality in all dose groups during the study. Histiocytomas were found at injection sites in male rats (statistically significant) and male mice (not statistically significant) in acid vehicle containing groups. These tumors were not found in female animals, in saline control, or insulin comparator groups using a different vehicle. The relevance of these findings to humans is unknown.

Insulin glargine was not mutagenic in tests for detection of gene mutations in bacteria and mammalian cells (Ames and HGPRT test) and in tests for detection of chromosomal aberrations (cytogenetics in vitro in V79 cells and in vivo in Chinese hamsters).

In a combined fertility and prenatal and postnatal study in male and female rats at subcutaneous doses up to 0.36 mg/kg/day, which was approximately 50 times the recommended human subcutaneous starting dose of 0.2 Units/kg/day (0.007 mg/kg/day), maternal toxicity due to dose-dependent hypoglycemia, including some deaths, was observed. Consequently, a reduction of the rearing rate occurred in the high-dose group only. Similar effects were observed with NPH insulin.

The efficacy of TOUJEO given once daily was compared to that of once-daily LANTUS in 26-week, open-label, randomized, active-control, parallel studies of 546 adult patients and 463 pediatric patients with type 1 diabetes mellitus and 2,474 patients with type 2 diabetes mellitus (Tables 4 and 5). At trial end, the reduction in glycated hemoglobin (HbA1c) and fasting plasma glucose with TOUJEO titrated to goal was similar to that with LANTUS titrated to goal. At the end of the trial, depending on the patient population and concomitant therapy, patients were receiving a higher dose of TOUJEO than LANTUS.

Adult Patients with Type 1 Diabetes

In an open-label, controlled study (Study A), patients with type 1 diabetes (n=546), were randomized to basal-bolus treatment with TOUJEO or LANTUS and treated for 26 weeks. TOUJEO and LANTUS were administered once daily in the morning (time period covering from pre-breakfast until pre-lunch) or in the evening (time period defined as prior to the evening meal until at bedtime). A mealtime insulin analogue was administered before each meal. Mean age was 47 years and mean duration of diabetes was 21 years. Fifty-seven percent were male, 85% were White, 5% Black or African American, and 5% were Hispanic or Latino; 32% of patients had GFR >90 mL/min/1.73 m2. The mean BMI was approximately 27.6 kg/m2. At week 26, treatment with TOUJEO provided a mean reduction in HbA1c that met the prespecified noninferiority margin of 0.4% (Table 4). Patients treated with TOUJEO used 18% more basal insulin than patients treated with LANTUS. There were no clinically important differences in glycemic control when TOUJEO was administered once daily in the morning or in the evening. There were no clinically important differences in body weight between treatment groups.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 4 : Type 1 Diabetes Mellitus – Adult Patients (TOUJEO plus mealtime insulin versus LANTUS plus mealtime insulin)</span> </caption> <col align="left" valign="middle" width="54%"/> <col align="center" valign="middle" width="23%"/> <col align="center" valign="middle" width="23%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center">TOUJEO + Mealtime Insulin<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a></th><th align="center" class="Rrule">LANTUS + Mealtime Insulin<a class="Sup" href="#footnote-3">*</a></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>"mealtime insulin" refers to insulin glulisine, insulin lispro or insulin aspart.</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>mITT: Modified intention-to-treat population.</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">‡</a> </dt> <dd>Treatment difference: TOUJEO – LANTUS.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Lrule Rrule">Treatment duration</td><td align="center" class="Rrule" colspan="2">26 weeks</td> </tr> <tr> <td align="left" class="Lrule Rrule">Treatment in combination with</td><td align="center" class="Rrule" colspan="2">Fast-acting insulin analogue</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Number of subjects treated (mITT<a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a>)</td><td align="center">273</td><td align="center" class="Rrule">273</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule"><span class="Bold">HbA1c (%)</span></td><td align="center" class="Rrule" colspan="2"></td> </tr> <tr> <td align="left" class="Lrule Rrule">Baseline mean</td><td align="center">8.13</td><td align="center" class="Rrule">8.12</td> </tr> <tr> <td align="left" class="Lrule Rrule">Adjusted mean change from baseline</td><td align="center">-0.40</td><td align="center" class="Rrule">-0.44</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Adjusted mean difference<a class="Sup" href="#footnote-5" name="footnote-reference-5">‡</a> <br/>[95% Confidence Interval]</td><td align="center" class="Rrule" colspan="2">0.04<br/>[-0.10 to 0.18]</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule"><span class="Bold">Fasting Plasma Glucose mg/dL</span></td><td align="center"></td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule">Baseline mean</td><td align="center">186</td><td align="center" class="Rrule">199</td> </tr> <tr> <td align="left" class="Lrule Rrule">Adjusted mean change from baseline</td><td align="center">-17</td><td align="center" class="Rrule">-20</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Adjusted mean difference<a class="Sup" href="#footnote-5">‡</a> <br/>[95% Confidence Interval]</td><td align="center" class="Rrule" colspan="2">3<br/>[-10 to 16]</td> </tr> </tbody> </table></div>

Pediatric Patients with Type 1 Diabetes

The efficacy of TOUJEO was evaluated in a 26-week, randomized, open-label, multicenter trial (Study B) in 463 pediatric patients with type 1 diabetes mellitus. Patients were randomized to basal-bolus treatment with TOUJEO or LANTUS and treated for 26 weeks. TOUJEO and LANTUS were administered once daily in the morning or in the evening. A mealtime insulin analogue was administered before each meal.

The mean age of the trial population was 13 years; 31% were <12 years of age, 69% were ages ≥12 years of age. The mean duration of diabetes was 6 years. Of the 463 pediatric patients, 51% were male, 92% were White, 3% were Black or African American, and 30% were Hispanic or Latino. The mean baseline BMI percentile was 68.32.

At week 26, the difference in HbA1c reduction from baseline between TOUJEO and LANTUS was 0.02% with a 95% confidence interval (-0.16%; 0.20%) and met the prespecified noninferiority margin (0.3%). The results are presented in Table 5.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 5: Type 1 Diabetes Mellitus – Pediatric Patients at 26 weeks (TOUJEO plus mealtime insulin versus LANTUS plus mealtime insulin)</span> </caption> <col align="left" valign="middle" width="54%"/> <col align="center" valign="middle" width="23%"/> <col align="center" valign="middle" width="23%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center">TOUJEO + Mealtime Insulin<a class="Sup" href="#footnote-6" name="footnote-reference-6">*</a></th><th align="center" class="Rrule">LANTUS + Mealtime Insulin<a class="Sup" href="#footnote-6">*</a></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-6" name="footnote-6">*</a> </dt> <dd>"mealtime insulin" refers to insulin glulisine, insulin lispro or insulin aspart.</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">†</a> </dt> <dd>ITT: Intention-to-treat: all randomized subjects.</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">‡</a> </dt> <dd>At week 26, change in HbA1c was missing for 3.9% and 4.3% of subjects, and change in FPG was missing for 12.4% and 12.2% of subjects, in TOUJEO and LANTUS respectively. Missing values were imputed with return-to-baseline method for subjects who permanently discontinued the treatment.</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">§</a> </dt> <dd>Treatment difference: TOUJEO – LANTUS.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Number of subjects (ITT<a class="Sup" href="#footnote-7" name="footnote-reference-7">†</a>)</td><td align="center">233</td><td align="center" class="Rrule">230</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule"><span class="Bold">HbA1c (%)</span><a class="Sup" href="#footnote-8" name="footnote-reference-8">‡</a></td><td align="center" class="Rrule" colspan="2"></td> </tr> <tr> <td align="left" class="Lrule Rrule">Baseline mean</td><td align="center">8.65</td><td align="center" class="Rrule">8.61</td> </tr> <tr> <td align="left" class="Lrule Rrule">Adjusted Mean change from baseline</td><td align="center">-0.386</td><td align="center" class="Rrule">-0.404</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Adjusted Mean difference<a class="Sup" href="#footnote-9" name="footnote-reference-9">§</a> <br/>[95% Confidence Interval]</td><td align="center" class="Rrule" colspan="2">0.018<br/> [-0.159, 0.195]</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule"><span class="Bold">Fasting Plasma Glucose (mg/dL)</span><a class="Sup" href="#footnote-8">‡</a></td><td align="center"></td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule">Baseline mean</td><td align="center">202.70</td><td align="center" class="Rrule">204.51</td> </tr> <tr> <td align="left" class="Lrule Rrule">Adjusted Mean change from baseline</td><td align="center">-10.447</td><td align="center" class="Rrule">-10.633</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Adjusted Mean difference<a class="Sup" href="#footnote-9">§</a> <br/>[95% Confidence Interval]</td><td align="center" class="Rrule" colspan="2">0.185<br/>[-18.131, 18.501]</td> </tr> </tbody> </table></div>

In a 26-week open-label, controlled study (Study C, n=804), adults with type 2 diabetes were randomized to once-daily treatment in the evening with either TOUJEO or LANTUS. Short-acting mealtime insulin analogues with or without metformin were also administered. The average age was 60 years. The majority of patients were White (92%) and 53% were male; 20% of patients had GFR >90 mL/min/1.73 m2. The mean BMI was approximately 36.6 kg/m2. At week 26, treatment with TOUJEO provided a mean reduction in HbA1c that met the prespecified noninferiority margin of 0.4% compared to LANTUS (Table 6). Patients treated with TOUJEO used 11% more basal insulin than patients treated with LANTUS. There were no clinically important differences in body weight between treatment groups.

In two open-label, controlled studies (n=1670), adults with type 2 diabetes mellitus were randomized to either TOUJEO or LANTUS once daily for 26 weeks as part of a regimen of combination therapy with noninsulin antidiabetic drugs. At the time of randomization, 808 patients were treated with basal insulin for more than 6 months (Study D) and 862 patients were insulin-naive (Study E).

In Study D, the average age was 58.2 years. The majority of patients were White (94%) and 46% were male; 33% of patients had GFR >90 mL/min/1.73 m2. The mean BMI was approximately 34.8 kg/m2. At week 26, treatment with TOUJEO provided a mean reduction in HbA1c that met the prespecified noninferiority margin of 0.4% compared to LANTUS (Table 6). Patients treated with TOUJEO used 12% more basal insulin than patients treated with LANTUS. There were no clinically important differences in body weight between treatment groups.

In Study E, the average age was 58 years. The majority of patients were White (78%) and 58% were male; 29% of patients had GFR >90 mL/min/1.73 m2. The mean BMI was approximately 33 kg/m2. At week 26, treatment with TOUJEO provided a mean reduction in HbA1c that met the prespecified noninferiority margin compared to LANTUS (Table 6). Patients treated with TOUJEO used 15% more basal insulin than patients treated with LANTUS. There were no clinically important differences in body weight between treatment groups.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 6: Type 2 Diabetes Mellitus – Adult</span> </caption> <col align="left" valign="top" width="19%"/> <col align="center" valign="middle" width="13%"/> <col align="center" valign="middle" width="13%"/> <col align="center" valign="middle" width="13%"/> <col align="center" valign="middle" width="14%"/> <col align="center" valign="middle" width="14%"/> <col align="center" valign="middle" width="14%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule" colspan="2">Study C</th><th align="center" class="Rrule" colspan="2">Study D</th><th align="center" class="Rrule" colspan="2">Study E</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-10" name="footnote-10">*</a> </dt> <dd>m-ITT population: Modified intention-to-treat population.</dd> <dt> <a href="#footnote-reference-11" name="footnote-11">†</a> </dt> <dd>Treatment difference: TOUJEO – LANTUS.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">Treatment duration</span></td><td align="center" class="Rrule" colspan="2">26 weeks</td><td align="center" class="Rrule" colspan="2">26 weeks</td><td align="center" class="Rrule" colspan="2">26 weeks</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Treatment in combination with</span></td><td align="center" class="Rrule" colspan="2">Mealtime insulin analog ± metformin</td><td align="center" class="Rrule" colspan="4">Noninsulin antidiabetic drugs</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"></td><td align="center" class="Rrule">TOUJEO</td><td align="center" class="Rrule">LANTUS</td><td align="center" class="Rrule">TOUJEO</td><td align="center" class="Rrule">LANTUS</td><td align="center" class="Rrule">TOUJEO</td><td align="center" class="Rrule">LANTUS</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Number of patients treated<a class="Sup" href="#footnote-10" name="footnote-reference-10">*</a></td><td align="center" class="Rrule">404</td><td align="center" class="Rrule">400</td><td align="center" class="Rrule">403</td><td align="center" class="Rrule">405</td><td align="center" class="Rrule">432</td><td align="center" class="Rrule">430</td> </tr> <tr> <td align="left" class="Lrule Rrule"><span class="Bold">HbA1c (%)</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule">Baseline mean</td><td align="center" class="Rrule">8.13</td><td align="center" class="Rrule">8.14</td><td align="center" class="Rrule">8.27</td><td align="center" class="Rrule">8.22</td><td align="center" class="Rrule">8.49</td><td align="center" class="Rrule">8.58</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Adjusted mean change from baseline</td><td align="center" class="Rrule" valign="middle">-0.90</td><td align="center" class="Rrule" valign="middle">-0.87</td><td align="center" class="Rrule" valign="middle">-0.73</td><td align="center" class="Rrule" valign="middle">-0.70</td><td align="center" class="Rrule" valign="middle">-1.42</td><td align="center" class="Rrule" valign="middle">-1.46</td> </tr> <tr> <td align="left" class="Lrule Rrule">Adjusted mean difference<a class="Sup" href="#footnote-11" name="footnote-reference-11">†</a></td><td align="center" class="Rrule" colspan="2" valign="bottom">-0.03</td><td align="center" class="Rrule" colspan="2" valign="bottom">-0.03</td><td align="center" class="Rrule" colspan="2" valign="bottom">0.04</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">[95% Confidence interval]</td><td align="center" class="Rrule" colspan="2" valign="bottom">[-0.14 to 0.08]</td><td align="center" class="Rrule" colspan="2" valign="bottom">[-0.17 to 0.10]</td><td align="center" class="Rrule" colspan="2" valign="bottom">[-0.09 to 0.17]</td> </tr> <tr> <td align="left" class="Lrule Rrule"><span class="Bold">Fasting Plasma Glucose (mg/dL)</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule">Baseline mean</td><td align="center" class="Rrule">157</td><td align="center" class="Rrule">160</td><td align="center" class="Rrule">149</td><td align="center" class="Rrule">142</td><td align="center" class="Rrule">179</td><td align="center" class="Rrule">184</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Adjusted mean change from baseline</td><td align="center" class="Rrule" valign="middle">-29</td><td align="center" class="Rrule" valign="middle">-30</td><td align="center" class="Rrule" valign="middle">-18</td><td align="center" class="Rrule" valign="middle">-22</td><td align="center" class="Rrule" valign="middle">-61</td><td align="center" class="Rrule" valign="middle">-68</td> </tr> <tr> <td align="left" class="Lrule Rrule">Adjusted mean difference<a class="Sup" href="#footnote-11">†</a></td><td align="center" class="Rrule" colspan="2" valign="bottom">0.8</td><td align="center" class="Rrule" colspan="2" valign="bottom">3</td><td align="center" class="Rrule" colspan="2" valign="bottom">7</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">[95% Confidence interval]</td><td align="center" class="Rrule" colspan="2" valign="bottom">[-5 to 7]</td><td align="center" class="Rrule" colspan="2" valign="bottom">[-3 to 9]</td><td align="center" class="Rrule" colspan="2" valign="bottom">[2 to 12]</td> </tr> </tbody> </table></div>

Safety Outcomes Trial

No clinical studies to establish the cardiovascular safety of TOUJEO have been conducted. A cardiovascular outcomes trial, ORIGIN, has been conducted with LANTUS. It is unknown whether the results of ORIGIN can be applied to TOUJEO.

The Outcome Reduction with Initial Glargine Intervention trial (i.e., ORIGIN) was an open-label, randomized, 12,537 patient study that compared LANTUS to standard care on the time to first occurrence of a major adverse cardiovascular event (MACE). MACE was defined as the composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. The incidence of MACE was similar between LANTUS and standard care in ORIGIN (Hazard Ratio [95% CI] for MACE; 1.02 [0.94, 1.11]).

In the ORIGIN trial, the overall incidence of cancer (all types combined) (Hazard Ratio [95% CI]; 0.99 [0.88, 1.11]) or death from cancer (Hazard Ratio [95% CI]; 0.94 [0.77, 1.15]) was also similar between treatment groups.

TOUJEO (insulin glargine) injection, 300 units/mL (U-300), is a clear and colorless solution and is available as:

<div class="scrollingtable"><table width="75%"> <col align="left" valign="middle" width="15%"/> <col align="center" valign="middle" width="14%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="14%"/> <col align="center" valign="middle" width="14%"/> <col align="center" valign="middle" width="14%"/> <col align="center" valign="middle" width="14%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">TOUJEO</th><th align="center" class="Rrule">Total volume</th><th align="center" class="Rrule">Total units available in presentation</th><th align="center" class="Rrule">Max dose per injection</th><th align="center" class="Rrule">Dose increment</th><th align="center" class="Rrule">NDC number</th><th align="center" class="Rrule">Package size</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">SoloStar single-patient-use prefilled pen</td><td align="center" class="Rrule">1.5 mL</td><td align="center" class="Rrule">450 units</td><td align="center" class="Rrule">80 units</td><td align="center" class="Rrule">1 unit</td><td align="center" class="Rrule">0024-5869-03</td><td align="center" class="Rrule">3 pens/pack</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Max SoloStar single-patient-use prefilled pen</td><td align="center" class="Rrule">3 mL</td><td align="center" class="Rrule">900 units</td><td align="center" class="Rrule">160 units</td><td align="center" class="Rrule">2 units</td><td align="center" class="Rrule">0024-5871-02</td><td align="center" class="Rrule">2 pens/pack</td> </tr> </tbody> </table></div>

Needles are not included in the packs of TOUJEO SoloStar or TOUJEO Max SoloStar single-patient-use prefilled pen.

BD (such as BD Ultra-Fine®), Ypsomed (such as Clickfine®) or Owen Mumford (such as Unifine® Pentips®) needles‡ can be used in conjunction with TOUJEO SoloStar or TOUJEO Max SoloStar single-patient-use prefilled pen and are sold separately.

A new sterile needle must be attached before each injection. TOUJEO SoloStar or TOUJEO Max SoloStar single-patient-use prefilled pens must never be shared between patients, even if the needle is changed.

Dispense in the original sealed carton with the enclosed Instructions for Use.

TOUJEO SoloStar or TOUJEO Max SoloStar prefilled pen should not be stored in the freezer and should not be allowed to freeze. Discard TOUJEO prefilled pen if it has been frozen. Protect TOUJEO SoloStar/TOUJEO Max SoloStar from direct heat and light.

Storage conditions are summarized in the following table:

<div class="scrollingtable"><table width="65%"> <col align="left" valign="top" width="30%"/> <col align="center" valign="top" width="30%"/> <col align="center" valign="top" width="40%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">TOUJEO</th><th align="center" class="Rrule" valign="middle">Not in-use (unopened) Refrigerated <br/>36°F–46°F (2°C–8°C)</th><th align="center" class="Rrule" valign="middle">In-use (opened)<a class="Sup" href="#footnote-12" name="footnote-reference-12">*</a> <br/> Room temperature only<br/>(Do not refrigerate)<br/>up to 86°F (30°C)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-12" name="footnote-12">*</a> </dt> <dd>To prevent degradation, always store the prefilled pens with the cap on during in-use period. </dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">1.5 mL SoloStar single-patient-use prefilled pen</td><td align="center" class="Rrule">Until expiration date</td><td align="center" class="Rrule">56 days<a class="Sup" href="#footnote-12">*</a></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">3 mL Max SoloStar single-patient-use prefilled pen</td><td align="center" class="Rrule">Until expiration date</td><td align="center" class="Rrule">56 days<a class="Sup" href="#footnote-12">*</a></td> </tr> </tbody> </table></div>

Never Share a TOUJEO SoloStar or TOUJEO Max SoloStar Pen Between Patients

Advise patients that they must never share TOUJEO SoloStar or TOUJEO Max SoloStar pen with another person even if the needle is changed. Pen 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. Inform patients of the symptoms of hypoglycemia (e.g., impaired ability to concentrate and react). This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery [see Warnings and Precautions (5.2, 5.3)].

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)].

Inform patients that if they change to TOUJEO from other basal insulins they may experience higher average fasting plasma glucose levels in the first weeks of therapy. Advise patients to monitor glucose daily when initiating TOUJEO [see Warnings and Precautions (5.2)].

Hypoglycemia Due to Medication Errors

Instruct patients to always check the insulin label before each injection [see Warnings and Precautions (5.4)]. The "300 units/mL (U-300)" is highlighted in honey gold on the labels of TOUJEO and TOUJEO Max SoloStar single-patient-use prefilled pens.

Inform patients that TOUJEO contains 300 units of insulin glargine per mL (U-300) compared to formulations of insulin glargine that contain 100 units/mL (U-100). To avoid dosing errors and potential overdose, instruct patients to never use a syringe to remove TOUJEO from the TOUJEO SoloStar or TOUJEO Max SoloStar single-patient-use prefilled pen [see Warnings and Precautions (5.4)].

Inform patients that the dose counter of TOUJEO SoloStar or TOUJEO Max SoloStar single-patient-use prefilled pen shows the number of units of TOUJEO to be injected and no dose recalculation is required [see Dosage and Administration (2.1, 2.4)].

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions have occurred with TOUJEO. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.5)].

Manufactured by:sanofi-aventis U.S. LLCMorristown, NJ 07960A SANOFI COMPANYU.S. License No. 1752

{ "type": "p", "children": [], "text": "Manufactured by:sanofi-aventis U.S. LLCMorristown, NJ 07960A SANOFI COMPANYU.S. License No. 1752" }

For patent information: https://www.sanofi.us/en/products-and-resources/patents

{ "type": "p", "children": [], "text": "For patent information: https://www.sanofi.us/en/products-and-resources/patents" }

©2025 sanofi-aventis U.S. LLC

{ "type": "p", "children": [], "text": "©2025 sanofi-aventis U.S. LLC" }

LANTUS, TOUJEO, SoloStar, and TOUJEO Max SoloStar are registered trademarks of sanofi-aventis U.S. LLC.

{ "type": "p", "children": [], "text": "LANTUS, TOUJEO, SoloStar, and TOUJEO Max SoloStar are registered trademarks of sanofi-aventis U.S. LLC." }

‡Other brands listed are the registered trademarks of their respective owners and are not trademarks of sanofi-aventis U.S. LLC.

{ "type": "p", "children": [], "text": "\n‡Other brands listed are the registered trademarks of their respective owners and are not trademarks of sanofi-aventis U.S. LLC." }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="80%"/> <col align="right" valign="top" width="20%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="2">This Patient Information has been approved by the U.S. Food and Drug Administration<br/>Revised: May 2025</td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">Patient Information<br/>TOUJEO<span class="Sup">®</span> U-300 [too-JAY-oh] <br/>(insulin glargine)<br/>injection, for subcutaneous use<br/>300 units/mL (U-300)</span> </p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">Do not share your TOUJEO SoloStar<span class="Sup">®</span> or TOUJEO Max SoloStar<span class="Sup">®</span> pen 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.</span> </p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">What is TOUJEO?</span> </p> <ul class="Disc"> <li>TOUJEO is a long-acting man-made insulin used to control high blood sugar in adults and children who are 6 years of age and older with diabetes mellitus.</li> <li>TOUJEO is not for the treatment of diabetic ketoacidosis.</li> <li>It is not known if TOUJEO is safe and effective in children under 6 years of age.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">Who should not use TOUJEO?</span> </p> <p> <span class="Bold">Do not use TOUJEO if you:</span> </p> <ul class="Disc"> <li>are having an episode of low blood sugar (hypoglycemia).</li> <li>have an allergy to insulin glargine or any of the ingredients in TOUJEO. See the end of this Patient Information leaflet for a complete list of ingredients in TOUJEO.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">What should I tell my healthcare provider before using TOUJEO?</span> </p> <p> <span class="Bold">Before using TOUJEO, tell your healthcare provider about all your medical conditions, including if you:</span> </p> <ul class="Disc"> <li>have liver or kidney problems.</li> <li>take other medicines, especially ones called TZDs (thiazolidinediones).</li> <li>have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with TOUJEO.</li> <li>are pregnant, planning to become pregnant, or are breastfeeding. It is not known if TOUJEO may harm your unborn or breastfeeding baby.</li> </ul> <p>Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.</p> <p> <span class="Bold">Before you start using TOUJEO, talk to your healthcare provider about low blood sugar and how to manage it.</span> </p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">How should I use TOUJEO?</span> </p> <ul class="Disc"> <li>TOUJEO is available in 2 single-patient-use prefilled pens: TOUJEO SoloStar and TOUJEO Max SoloStar. Your healthcare provider will tell you which TOUJEO pen is right for you.</li> <li>Read the detailed <span class="Bold">Instructions for Use</span> that come with your TOUJEO SoloStar or TOUJEO Max SoloStar single-patient-use prefilled pen.</li> <li>Use TOUJEO exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much TOUJEO to use and when to use it.</li> <li>Know the amount of TOUJEO you use. <span class="Bold">Do not</span> change the amount of TOUJEO you use unless your healthcare provider tells you to.</li> <li>Check your insulin label each time you give your injection to make sure you are using the correct insulin.</li> <li> <span class="Bold">Do not</span> use a syringe to remove TOUJEO from your TOUJEO SoloStar or TOUJEO Max SoloStar single-patient-use prefilled pen. This can cause you to give yourself too much insulin. TOUJEO has 3 times as much insulin (300 units/mL) in 1 mL as compared to other insulin glargine products (U-100 units/mL) pens.</li> <li> <span class="Bold">Do not</span> re-use needles. Always use a new needle for each injection. Reusing needles increases your chance of having blocked needles, which can cause you to get the wrong dose of TOUJEO. Using a new needle for each injection also lowers your risk of getting an infection. If your needle is blocked, follow the instructions in <span class="Bold">Step 3</span> of the <span class="Bold">Instructions for Use</span>.</li> <li>TOUJEO should be used 1 time each day and at the same time each day.</li> <li>TOUJEO is injected under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen).</li> <li> <span class="Bold">Do not</span> use TOUJEO in an insulin pump or inject TOUJEO into your vein (intravenously).</li> <li> <span class="Bold">Change (rotate) your injection sites within the area you choose with each dose</span> to reduce your risk of getting pits or thickening of the skin (lipodystrophy) and lumps in the skin (localized cutaneous amyloidosis) at the injection sites.<ul class="Circle"> <li> <span class="Bold">Do not</span> use the exact same spot for each injection.</li> <li> <span class="Bold">Do not</span> inject where the skin has pits, is thickened, or has lumps.</li> <li> <span class="Bold">Do not</span> inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.</li> </ul> </li> <li> <span class="Bold">Do not</span> mix TOUJEO with any other type of insulin or liquid medicine.</li> <li> <span class="Bold">Check your blood sugar levels.</span> Ask your healthcare provider what your blood sugar should be and when you should check your blood sugar levels.</li> </ul> <p> <span class="Bold">Keep TOUJEO and all medicines out of the reach of children.</span> </p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">Your dose of TOUJEO may need to change because of:</span> </p> <ul class="Disc"> <li>a change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">What should I avoid while using TOUJEO?</span> </p> <p> <span class="Bold">While using TOUJEO do not:</span> </p> <ul class="Disc"> <li>drive or operate heavy machinery, until you know how TOUJEO affects you.</li> <li>drink alcohol or use over-the-counter medicines that contain alcohol.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">What are the possible side effects of TOUJEO?</span> </p> <p> <span class="Bold">TOUJEO may cause serious side effects that can lead to death, including:</span> </p> <ul class="Disc"> <li> <span class="Bold">low blood sugar (hypoglycemia).</span> Signs and symptoms that may indicate low blood sugar include:<ul class="Circle"> <li>dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood change, and hunger.</li> </ul> </li> <li> <span class="Bold">severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or symptoms of a severe allergic reaction:</span> <ul class="Circle"> <li>a rash over your whole body, trouble breathing, a fast heartbeat, or sweating.</li> </ul> </li> <li> <span class="Bold">low potassium in your blood (hypokalemia).</span> </li> <li> <span class="Bold">heart failure.</span> Taking certain diabetes pills called TZDs (thiazolidinediones) with TOUJEO may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with TOUJEO. Your healthcare provider should monitor you closely while you are taking TZDs with TOUJEO. Tell your healthcare provider if you have any new or worse symptoms of heart failure including:<ul class="Circle"> <li>shortness of breath, swelling of your ankles or feet, sudden weight gain.</li> </ul> <p class="First">Treatment with TZDs and TOUJEO may need to be changed or stopped by your healthcare provider if you have new or worse heart failure.</p> </li> </ul> <p> <span class="Bold">Get emergency medical help if you have:</span> </p> <ul class="Disc"> <li>trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion.</li> </ul> <p> <span class="Bold">The most common side effects of TOUJEO include:</span> </p> <ul class="Disc"> <li>low blood sugar (hypoglycemia), weight gain, itching, rash, swelling, allergic reactions, including reactions at your injection site, skin thickening or pits at the injection site (lipodystrophy).</li> </ul> <p> <span class="Bold">These are not all the possible side effects of TOUJEO.</span> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">General information about the safe and effective use of TOUJEO.</span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. <span class="Bold">Do not</span> use TOUJEO for a condition for which it was not prescribed. <span class="Bold">Do not</span> give TOUJEO to other people, even if they have the same symptoms that you have. It may harm them.</p> <p>This Patient Information leaflet summarizes the most important information about TOUJEO. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about TOUJEO that is written for health professionals.</p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">What are the ingredients in TOUJEO?</span> </p> <ul class="Disc"> <li> <span class="Bold">Active ingredient:</span> insulin glargine</li> <li> <span class="Bold">Inactive ingredients:</span> glycerin, metacresol, zinc and Water for Injection, USP. Hydrochloric acid and sodium hydroxide may be added to adjust the pH.</li> </ul> </td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="2"> <p class="First">Manufactured by: sanofi-aventis U.S. LLC, Morristown, NJ 07960, A SANOFI COMPANY.<br/>U.S. License No. 1752 <br/>For more information, go to www.TOUJEO.com or call 1-800-633-1610.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"80%\"/>\n<col align=\"right\" valign=\"top\" width=\"20%\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" colspan=\"2\">This Patient Information has been approved by the U.S. Food and Drug Administration<br/>Revised: May 2025</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"center\" class=\"Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Patient Information<br/>TOUJEO<span class=\"Sup\">®</span> U-300 [too-JAY-oh] <br/>(insulin glargine)<br/>injection, for subcutaneous use<br/>300 units/mL (U-300)</span>\n</p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Do not share your TOUJEO SoloStar<span class=\"Sup\">®</span> or TOUJEO Max SoloStar<span class=\"Sup\">®</span> pen 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.</span>\n</p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What is TOUJEO?</span>\n</p>\n<ul class=\"Disc\">\n<li>TOUJEO is a long-acting man-made insulin used to control high blood sugar in adults and children who are 6 years of age and older with diabetes mellitus.</li>\n<li>TOUJEO is not for the treatment of diabetic ketoacidosis.</li>\n<li>It is not known if TOUJEO is safe and effective in children under 6 years of age.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Who should not use TOUJEO?</span>\n</p>\n<p>\n<span class=\"Bold\">Do not use TOUJEO if you:</span>\n</p>\n<ul class=\"Disc\">\n<li>are having an episode of low blood sugar (hypoglycemia).</li>\n<li>have an allergy to insulin glargine or any of the ingredients in TOUJEO. See the end of this Patient Information leaflet for a complete list of ingredients in TOUJEO.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What should I tell my healthcare provider before using TOUJEO?</span>\n</p>\n<p>\n<span class=\"Bold\">Before using TOUJEO, tell your healthcare provider about all your medical conditions, including if you:</span>\n</p>\n<ul class=\"Disc\">\n<li>have liver or kidney problems.</li>\n<li>take other medicines, especially ones called TZDs (thiazolidinediones).</li>\n<li>have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with TOUJEO.</li>\n<li>are pregnant, planning to become pregnant, or are breastfeeding. It is not known if TOUJEO may harm your unborn or breastfeeding baby.</li>\n</ul>\n<p>Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.</p>\n<p>\n<span class=\"Bold\">Before you start using TOUJEO, talk to your healthcare provider about low blood sugar and how to manage it.</span>\n</p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">How should I use TOUJEO?</span>\n</p>\n<ul class=\"Disc\">\n<li>TOUJEO is available in 2 single-patient-use prefilled pens: TOUJEO SoloStar and TOUJEO Max SoloStar. Your healthcare provider will tell you which TOUJEO pen is right for you.</li>\n<li>Read the detailed <span class=\"Bold\">Instructions for Use</span> that come with your TOUJEO SoloStar or TOUJEO Max SoloStar single-patient-use prefilled pen.</li>\n<li>Use TOUJEO exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much TOUJEO to use and when to use it.</li>\n<li>Know the amount of TOUJEO you use. <span class=\"Bold\">Do not</span> change the amount of TOUJEO you use unless your healthcare provider tells you to.</li>\n<li>Check your insulin label each time you give your injection to make sure you are using the correct insulin.</li>\n<li>\n<span class=\"Bold\">Do not</span> use a syringe to remove TOUJEO from your TOUJEO SoloStar or TOUJEO Max SoloStar single-patient-use prefilled pen. This can cause you to give yourself too much insulin. TOUJEO has 3 times as much insulin (300 units/mL) in 1 mL as compared to other insulin glargine products (U-100 units/mL) pens.</li>\n<li>\n<span class=\"Bold\">Do not</span> re-use needles. Always use a new needle for each injection. Reusing needles increases your chance of having blocked needles, which can cause you to get the wrong dose of TOUJEO. Using a new needle for each injection also lowers your risk of getting an infection. If your needle is blocked, follow the instructions in <span class=\"Bold\">Step 3</span> of the <span class=\"Bold\">Instructions for Use</span>.</li>\n<li>TOUJEO should be used 1 time each day and at the same time each day.</li>\n<li>TOUJEO is injected under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen).</li>\n<li>\n<span class=\"Bold\">Do not</span> use TOUJEO in an insulin pump or inject TOUJEO into your vein (intravenously).</li>\n<li>\n<span class=\"Bold\">Change (rotate) your injection sites within the area you choose with each dose</span> to reduce your risk of getting pits or thickening of the skin (lipodystrophy) and lumps in the skin (localized cutaneous amyloidosis) at the injection sites.<ul class=\"Circle\">\n<li>\n<span class=\"Bold\">Do not</span> use the exact same spot for each injection.</li>\n<li>\n<span class=\"Bold\">Do not</span> inject where the skin has pits, is thickened, or has lumps.</li>\n<li>\n<span class=\"Bold\">Do not</span> inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">Do not</span> mix TOUJEO with any other type of insulin or liquid medicine.</li>\n<li>\n<span class=\"Bold\">Check your blood sugar levels.</span> Ask your healthcare provider what your blood sugar should be and when you should check your blood sugar levels.</li>\n</ul>\n<p>\n<span class=\"Bold\">Keep TOUJEO and all medicines out of the reach of children.</span>\n</p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Your dose of TOUJEO may need to change because of:</span>\n</p>\n<ul class=\"Disc\">\n<li>a change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What should I avoid while using TOUJEO?</span>\n</p>\n<p>\n<span class=\"Bold\">While using TOUJEO do not:</span>\n</p>\n<ul class=\"Disc\">\n<li>drive or operate heavy machinery, until you know how TOUJEO affects you.</li>\n<li>drink alcohol or use over-the-counter medicines that contain alcohol.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of TOUJEO?</span>\n</p>\n<p>\n<span class=\"Bold\">TOUJEO may cause serious side effects that can lead to death, including:</span>\n</p>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">low blood sugar (hypoglycemia).</span> Signs and symptoms that may indicate low blood sugar include:<ul class=\"Circle\">\n<li>dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood change, and hunger.</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or symptoms of a severe allergic reaction:</span>\n<ul class=\"Circle\">\n<li>a rash over your whole body, trouble breathing, a fast heartbeat, or sweating.</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">low potassium in your blood (hypokalemia).</span>\n</li>\n<li>\n<span class=\"Bold\">heart failure.</span> Taking certain diabetes pills called TZDs (thiazolidinediones) with TOUJEO may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with TOUJEO. Your healthcare provider should monitor you closely while you are taking TZDs with TOUJEO. Tell your healthcare provider if you have any new or worse symptoms of heart failure including:<ul class=\"Circle\">\n<li>shortness of breath, swelling of your ankles or feet, sudden weight gain.</li>\n</ul>\n<p class=\"First\">Treatment with TZDs and TOUJEO may need to be changed or stopped by your healthcare provider if you have new or worse heart failure.</p>\n</li>\n</ul>\n<p>\n<span class=\"Bold\">Get emergency medical help if you have:</span>\n</p>\n<ul class=\"Disc\">\n<li>trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion.</li>\n</ul>\n<p>\n<span class=\"Bold\">The most common side effects of TOUJEO include:</span>\n</p>\n<ul class=\"Disc\">\n<li>low blood sugar (hypoglycemia), weight gain, itching, rash, swelling, allergic reactions, including reactions at your injection site, skin thickening or pits at the injection site (lipodystrophy).</li>\n</ul>\n<p>\n<span class=\"Bold\">These are not all the possible side effects of TOUJEO.</span> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of TOUJEO.</span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. <span class=\"Bold\">Do not</span> use TOUJEO for a condition for which it was not prescribed. <span class=\"Bold\">Do not</span> give TOUJEO to other people, even if they have the same symptoms that you have. It may harm them.</p>\n<p>This Patient Information leaflet summarizes the most important information about TOUJEO. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about TOUJEO that is written for health professionals.</p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in TOUJEO?</span>\n</p>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Active ingredient:</span> insulin glargine</li>\n<li>\n<span class=\"Bold\">Inactive ingredients:</span> glycerin, metacresol, zinc and Water for Injection, USP. Hydrochloric acid and sodium hydroxide may be added to adjust the pH.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">Manufactured by: sanofi-aventis U.S. LLC, Morristown, NJ 07960, A SANOFI COMPANY.<br/>U.S. License No. 1752\t<br/>For more information, go to www.TOUJEO.com or call 1-800-633-1610.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

TOUJEO® U-300 SoloStar® [too-JAY-oh](insulin glargine) injection, for subcutaneous use 300 units/mL (U-300)1.5 mL single-patient-use prefilled pen

{ "type": "p", "children": [], "text": "\nTOUJEO® U-300 SoloStar® [too-JAY-oh](insulin glargine) injection, for subcutaneous use 300 units/mL (U-300)1.5 mL single-patient-use prefilled pen\n" }

Read this first

{ "type": "p", "children": [], "text": "Read this first" }

Do not share your TOUJEO SoloStar pen 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.

{ "type": "p", "children": [], "text": "\nDo not share your TOUJEO SoloStar pen 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.\n" }

TOUJEO contains 300 units/mL of insulin glargine

{ "type": "p", "children": [], "text": "\nTOUJEO contains 300 units/mL of insulin glargine\n" }

{ "type": "ul", "children": [ "\nDo not re-use needles. If you do, you might not get your dose (underdosing) or get too much (overdosing) as the needle could block.", "\nDo not use a syringe to remove insulin from your pen. If you do, you will get too much insulin. The scale on most syringes is made for U-100 (non-concentrated) insulin only.", "The dose selector of your TOUJEO SoloStar pen dials by 1 unit." ], "text": "" }

People who are blind or have vision problems should not use the TOUJEO SoloStar pen without help from a person trained to use the TOUJEO SoloStar pen.

{ "type": "p", "children": [], "text": "\nPeople who are blind or have vision problems should not use the TOUJEO SoloStar pen without help from a person trained to use the TOUJEO SoloStar pen.\n" }

Important information

{ "type": "p", "children": [], "text": "\nImportant information\n" }

{ "type": "ul", "children": [ "\nDo not use your pen if it is damaged or if you are not sure that it is working properly.", "Always perform a safety test (see Step 3).", "Always carry a spare pen and spare needles in case they are lost or stop working.", "Change (rotate) your injection sites within the area you choose for each dose (see \"Places to inject\")." ], "text": "" }

Learn to inject

{ "type": "p", "children": [], "text": "\nLearn to inject\n" }

{ "type": "ul", "children": [ "Talk with your healthcare provider about how to inject, before using your pen.", "Read all of these instructions before using your pen. If you do not follow all of these instructions, you may get too much or too little insulin." ], "text": "" }

Need help?

{ "type": "p", "children": [], "text": "\nNeed help?\n" }

If you have any questions about your pen or about diabetes, ask your healthcare provider, go to www.Toujeo.com or call sanofi-aventis at 1-800-633-1610.

{ "type": "p", "children": [], "text": "If you have any questions about your pen or about diabetes, ask your healthcare provider, go to www.Toujeo.com or call sanofi-aventis at 1-800-633-1610." }

Extra items you will need:

{ "type": "p", "children": [], "text": "\nExtra items you will need:\n" }

{ "type": "ul", "children": [ "a new sterile needle (not included with the pen) (see Step 2).", "an alcohol swab.", "a puncture-resistant container for used needles and pens (see \"Throwing your pen away\")." ], "text": "" }

Places to inject

{ "type": "p", "children": [], "text": "\nPlaces to inject\n" }

{ "type": "ul", "children": [ "Inject your insulin exactly as your healthcare provider has shown you.", "Inject your insulin under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen).", "Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting pits or thickening of the skin (lipodystrophy) and lumps in the skin (localized cutaneous amyloidosis) at the injection sites.", "\nDo not inject where the skin has pits, is thickened, or has lumps.\n\nDo not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.\n\n" ], "text": "" }

Get to know your pen

{ "type": "p", "children": [], "text": "\nGet to know your pen\n" }

Step 1: Check your pen

{ "type": "p", "children": [], "text": "\nStep 1: Check your pen\n" }

Take a new pen out of the refrigerator at least 1 hour before you inject. Cold insulin is more painful to inject.

{ "type": "p", "children": [], "text": "Take a new pen out of the refrigerator at least 1 hour before you inject. Cold insulin is more painful to inject." }

{ "type": "", "children": [], "text": "" }

If you have other injector pens

{ "type": "p", "children": [], "text": "\nIf you have other injector pens\n" }

{ "type": "ul", "children": [ "Making sure you have the correct medicine is especially important if you have other injector pens." ], "text": "" }

Step 2: Attach a new needle

{ "type": "p", "children": [], "text": "\nStep 2: Attach a new needle\n" }

{ "type": "ul", "children": [ "\nDo not re-use needles. Always use a new sterile needle for each injection. This helps stop blocked needles, contamination and infection.", "Always use needles* from BD (such as BD Ultra-Fine®), Ypsomed (such as Clickfine®), or Owen Mumford (such as Unifine® Pentips®)." ], "text": "" }

{ "type": "", "children": [], "text": "" }

Handling needles

{ "type": "p", "children": [], "text": "\nHandling needles\n" }

{ "type": "ul", "children": [ "Be careful when you are handling needles to help prevent accidental needle-stick injury. You may give other people a serious infection, or get a serious infection from them." ], "text": "" }

Step 3: Do a safety test

{ "type": "p", "children": [], "text": "\nStep 3: Do a safety test\n" }

Always do a safety test before each injection to:

{ "type": "p", "children": [], "text": "\nAlways do a safety test before each injection to:\n" }

{ "type": "ul", "children": [ "check your pen and the needle to make sure they are working properly.", "make sure that you get the correct insulin dose." ], "text": "" }

If the pen is new, you must perform safety tests before you use the pen for the first time until you see insulin coming out of the needle tip. If you see insulin coming out of the needle tip, the pen is ready to use. If you do not see insulin coming out before taking your dose, you could get an underdose or no insulin at all. This could cause high blood sugar.

{ "type": "p", "children": [], "text": "If the pen is new, you must perform safety tests before you use the pen for the first time until you see insulin coming out of the needle tip. If you see insulin coming out of the needle tip, the pen is ready to use. If you do not see insulin coming out before taking your dose, you could get an underdose or no insulin at all. This could cause high blood sugar." }

{ "type": "", "children": [], "text": "" }

If no insulin appears:

{ "type": "p", "children": [], "text": "\nIf no insulin appears:\n" }

{ "type": "ul", "children": [ "You may need to repeat this step up to 3 times before seeing insulin.", "If no insulin comes out after the third time, the needle may be blocked. If this happens:\n-\nchange the needle (see Step 6 and Step 2),\n-\nthen repeat the safety test (see Step 3).\n\n", "\nDo not use your pen if there is still no insulin coming out of the needle tip. Use a new pen.", "\nDo not use a syringe to remove insulin from your pen." ], "text": "" }

If you see air bubbles

{ "type": "p", "children": [], "text": "\nIf you see air bubbles\n" }

{ "type": "ul", "children": [ "You may see air bubbles in the insulin. This is normal, they will not harm you." ], "text": "" }

Step 4: Select the dose

{ "type": "p", "children": [], "text": "\nStep 4: Select the dose\n" }

{ "type": "ul", "children": [ "\nDo not select a dose or press the injection button without a needle attached. This may damage your pen.", "TOUJEO, SoloStar is made to deliver the number of insulin units that your healthcare provider prescribed. You do not need to do any dose calculations. \t\t\t\t\t\t\t", "The dose selector of your TOUJEO SoloStar pen dials by 1 unit." ], "text": "" }

{ "type": "", "children": [], "text": "" }

How to read the dose window

{ "type": "p", "children": [], "text": "\nHow to read the dose window\n" }

The dose selector dials by 1 unit.

{ "type": "p", "children": [], "text": "The dose selector dials by 1 unit." }

Even numbers are shown in line with the dose pointer:

{ "type": "p", "children": [], "text": "Even numbers are shown in line with the dose pointer:" }

                     30 units selected

{ "type": "p", "children": [], "text": "           \t\t\t\t\t\t\t\n          30 units selected\n" }

Odd numbers are shown as a line between even numbers:

{ "type": "p", "children": [], "text": "Odd numbers are shown as a line between even numbers:" }

                     29 units selected

{ "type": "p", "children": [], "text": "           \t\t\t\t\t\t\t\n          29 units selected\n" }

Units of insulin in your pen

{ "type": "p", "children": [], "text": "\nUnits of insulin in your pen\n" }

{ "type": "ul", "children": [ "Your pen contains a total of 450 units of insulin. You can select doses from 1 to 80 units. Each pen contains more than 1 dose.", "You can see roughly how many units of insulin are left by looking at where the plunger is on the insulin scale." ], "text": "" }

Step 5: Inject your dose

{ "type": "p", "children": [], "text": "\nStep 5: Inject your dose\n" }

If you find it hard to press the injection button in, do not force it as this may break your pen. See the section below for help.

{ "type": "p", "children": [], "text": "If you find it hard to press the injection button in, do not force it as this may break your pen. See the section below for help." }

{ "type": "", "children": [], "text": "" }

If you find it hard to press the injection button in:

{ "type": "p", "children": [], "text": "\nIf you find it hard to press the injection button in:\n" }

{ "type": "ul", "children": [ "Change the needle (see Step 6 and Step 2) then do a safety test (see Step 3).", "If you still find it hard to press in, get a new pen.", "Do not use a syringe to remove insulin from your pen." ], "text": "" }

Step 6: Remove the needle

{ "type": "p", "children": [], "text": "\nStep 6: Remove the needle\n" }

{ "type": "ul", "children": [ "\nTake care when handling needles to prevent needle injury and cross-infection.\n", "\nDo not put the inner needle cap back on.\n" ], "text": "" }

{ "type": "", "children": [], "text": "" }

Use by

{ "type": "p", "children": [], "text": "\nUse by\n" }

{ "type": "ul", "children": [ "Only use your pen for up to 56 days after its first use." ], "text": "" }

How to store your pen

{ "type": "p", "children": [], "text": "\nHow to store your pen \n" }

Before first use

{ "type": "p", "children": [], "text": "\nBefore first use\n" }

{ "type": "ul", "children": [ "Keep new pens in the refrigerator between 36°F and 46°F (2°C and 8°C).\n", "\nDo not freeze. Throw away your pen if it has been frozen (See \"Throwing your pen away\")." ], "text": "" }

After first use

{ "type": "p", "children": [], "text": "\nAfter first use\n" }

{ "type": "ul", "children": [ "Keep your pen at room temperature up to 86°F (30°C). \t\t\t\t\t\t\t", "Protect your pen from direct heat and light.", "\nDo not put your pen back in the refrigerator.", "\nDo not store your pen with the needle attached.", "Store your pen with the pen cap on.", "Keep TOUJEO SoloStar pens and needles out of the reach of children." ], "text": "" }

How to care for your pen

{ "type": "p", "children": [], "text": "\nHow to care for your pen\n" }

Handle your pen with care

{ "type": "p", "children": [], "text": "\nHandle your pen with care\n" }

{ "type": "ul", "children": [ "\nDo not drop your pen or knock it against hard surfaces.", "If you think that your pen may be damaged, do not try to fix it. Use a new one." ], "text": "" }

Protect your pen from dust and dirt

{ "type": "p", "children": [], "text": "\nProtect your pen from dust and dirt\n" }

{ "type": "ul", "children": [ "You can clean the outside of your pen by wiping it with a damp cloth (water only). Do not soak, wash or lubricate your pen. This may damage it." ], "text": "" }

Throwing your pen away

{ "type": "p", "children": [], "text": "\nThrowing your pen away\n" }

{ "type": "ul", "children": [ "The used TOUJEO SoloStar pen may be thrown away in your household trash after you have removed the needle.", "Put the used needle in a FDA-cleared sharps disposal container right away after use.\nDo not throw away (dispose of) needles in your household trash.", "If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:\n–\nmade of a heavy-duty plastic,\n–\ncan be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,\n–\nupright and stable during use,\n–\nleak-resistant, and\n–\nproperly labeled to warn of hazardous waste inside the container.\n\n", "When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.", "\nDo 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." ], "text": "" }

Manufactured by:sanofi-aventis U.S. LLCMorristown, NJ 07960A SANOFI COMPANYU.S. License No. 1752

{ "type": "p", "children": [], "text": "Manufactured by:sanofi-aventis U.S. LLCMorristown, NJ 07960A SANOFI COMPANYU.S. License No. 1752" }

©2025 sanofi-aventis U.S. LLC

{ "type": "p", "children": [], "text": "©2025 sanofi-aventis U.S. LLC" }

TOUJEO and SoloStar are registered trademarks of sanofi-aventis U.S. LLC.

{ "type": "p", "children": [], "text": "TOUJEO and SoloStar are registered trademarks of sanofi-aventis U.S. LLC." }

Other brands listed are the registered trademarks of their respective owners and are not trademarks of sanofi-aventis U.S. LLC.

{ "type": "p", "children": [], "text": "Other brands listed are the registered trademarks of their respective owners and are not trademarks of sanofi-aventis U.S. LLC." }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration." }

Revised: May 2025

{ "type": "p", "children": [], "text": "Revised: May 2025" }

TOUJEO U-300 Max SoloStar® [too-JAY-oh] (insulin glargine) injection, for subcutaneous use300 units/mL (U-300)3 mL single-patient-use prefilled pen

{ "type": "p", "children": [], "text": "\nTOUJEO U-300 Max SoloStar® [too-JAY-oh] (insulin glargine) injection, for subcutaneous use300 units/mL (U-300)3 mL single-patient-use prefilled pen\n" }

Read this first

{ "type": "p", "children": [], "text": "Read this first" }

Do not share your TOUJEO Max SoloStar pen 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.

{ "type": "p", "children": [], "text": "\nDo not share your TOUJEO Max SoloStar pen 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.\n" }

TOUJEO contains 300 units/mL of insulin glargine

{ "type": "p", "children": [], "text": "\nTOUJEO contains 300 units/mL of insulin glargine\n" }

{ "type": "ul", "children": [ "\nDo not re-use needles. If you do, you might not get your dose (underdosing) or get too much (overdosing) as the needle could block.", "\nDo not use a syringe to remove insulin from your pen. If you do, you will get too much insulin. The scale on most syringes is made for U-100 (non-concentrated) insulin only.", "The dose selector of your TOUJEO Max SoloStar pen dials by 2 units." ], "text": "" }

People who are blind or have vision problems should not use the TOUJEO Max SoloStar pen without help from a person trained to use the TOUJEO Max SoloStar pen.

{ "type": "p", "children": [], "text": "\nPeople who are blind or have vision problems should not use the TOUJEO Max SoloStar pen without help from a person trained to use the TOUJEO Max SoloStar pen.\n" }

Important information

{ "type": "p", "children": [], "text": "\nImportant information\n" }

{ "type": "ul", "children": [ "\nDo not use your pen if it is damaged or if you are not sure that it is working properly.", "Always perform a safety test (see Step 3).", "Always carry a spare pen and spare needles in case they are lost or stop working.", "Change (rotate) your injection sites within the area you choose for each dose (see \"Places to inject\")." ], "text": "" }

Learn to inject

{ "type": "p", "children": [], "text": "\nLearn to inject\n" }

{ "type": "ul", "children": [ "Talk with your healthcare provider about how to inject, before using your pen.", "Read all of these instructions before using your pen. If you do not follow all of these instructions, you may get too much or too little insulin." ], "text": "" }

Need help?

{ "type": "p", "children": [], "text": "\nNeed help?\n" }

If you have any questions about your pen or about diabetes, ask your healthcare provider, go to www.Toujeo.com or call sanofi-aventis at 1-800-633-1610.

{ "type": "p", "children": [], "text": "If you have any questions about your pen or about diabetes, ask your healthcare provider, go to www.Toujeo.com or call sanofi-aventis at 1-800-633-1610." }

Extra items you will need:

{ "type": "p", "children": [], "text": "\nExtra items you will need:\n" }

{ "type": "ul", "children": [ "a new sterile needle (not included with the pen) (see Step 2).", "an alcohol swab.", "a puncture-resistant container for used needles and pens (see \t\t\t\t\t\t\t\t\t\"Throwing your pen away\")." ], "text": "" }

Places to inject

{ "type": "p", "children": [], "text": "\nPlaces to inject\n" }

{ "type": "ul", "children": [ "Inject your insulin exactly as your healthcare provider has shown you.", "Inject your insulin under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen).", "Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting pits or thickening of the skin (lipodystrophy) and lumps in the skin (localized cutaneous amyloidosis) at the injection sites.", "\nDo not inject where the skin has pits, is thickened, or has lumps.\n\nDo not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.\n\n\n\n\n" ], "text": "" }

Get to know your pen

{ "type": "p", "children": [], "text": "\nGet to know your pen\n" }

Step 1: Check your pen

{ "type": "p", "children": [], "text": "\nStep 1: Check your pen\n" }

Take a new pen out of the refrigerator at least 1 hour before you inject. Cold insulin is more painful to inject.

{ "type": "p", "children": [], "text": "Take a new pen out of the refrigerator at least 1 hour before you inject. Cold insulin is more painful to inject." }

{ "type": "", "children": [], "text": "" }

If you have other injector pens

{ "type": "p", "children": [], "text": "\nIf you have other injector pens\n" }

{ "type": "ul", "children": [ "Making sure you have the correct medicine is especially important if you have other injector pens." ], "text": "" }

Step 2: Attach a new needle

{ "type": "p", "children": [], "text": "\nStep 2: Attach a new needle\n" }

{ "type": "ul", "children": [ "\nDo not re-use needles. Always use a new sterile needle for each injection. This helps stop blocked needles, contamination and infection.", "Always use needles* from BD (such as BD Ultra-Fine®), Ypsomed (such as Clickfine®), or Owen Mumford (such as Unifine® Pentips®) that are 8 mm long or shorter." ], "text": "" }

{ "type": "", "children": [], "text": "" }

Handling needles

{ "type": "p", "children": [], "text": "\nHandling needles\n" }

{ "type": "ul", "children": [ "Be careful when you are handling needles to help prevent accidental needle-stick injury. You may give other people a serious infection, or get a serious infection from them." ], "text": "" }

Step 3: Do a safety test

{ "type": "p", "children": [], "text": "\nStep 3: Do a safety test\n" }

Always do a safety test before each injection to:

{ "type": "p", "children": [], "text": "\nAlways do a safety test before each injection to:\n" }

{ "type": "ul", "children": [ "check your pen and the needle to make sure they are working properly.", "make sure that you get the correct insulin dose." ], "text": "" }

If the pen is new, you must perform safety tests before you use the pen for the first time until you see insulin coming out of the needle tip. If you see insulin coming out of the needle tip, the pen is ready to use. If you do not see insulin coming out before taking your dose, you could get an underdose or no insulin at all. This could cause high blood sugar.

{ "type": "p", "children": [], "text": "If the pen is new, you must perform safety tests before you use the pen for the first time until you see insulin coming out of the needle tip. If you see insulin coming out of the needle tip, the pen is ready to use. If you do not see insulin coming out before taking your dose, you could get an underdose or no insulin at all. This could cause high blood sugar." }

{ "type": "", "children": [], "text": "" }

If no insulin appears:

{ "type": "p", "children": [], "text": "\nIf no insulin appears:\n" }

{ "type": "ul", "children": [ "You may need to repeat this step up to 6 times before seeing insulin. \t\t\t\t\t\t\t\t\t", "If no insulin comes out after the sixth time, the needle may be blocked. If this happens:\n–\nchange the needle (see Step 6 and Step 2),\n–\nthen repeat the safety test (see Step 3).\n\n", "\nDo not use your pen if there is still no insulin coming out of the needle tip. Use a new pen.", "\nDo not use a syringe to remove insulin from your pen." ], "text": "" }

If you see air bubbles

{ "type": "p", "children": [], "text": "\nIf you see air bubbles\n" }

{ "type": "ul", "children": [ "You may see air bubbles in the insulin. This is normal, they will not harm you." ], "text": "" }

Step 4: Select the dose

{ "type": "p", "children": [], "text": "\nStep 4: Select the dose\n" }

{ "type": "ul", "children": [ "\nDo not select a dose or press the injection button without a needle attached. This may damage your pen.", "TOUJEO Max SoloStar is made to deliver the number of insulin units that your healthcare provider prescribed. You do not need to do any dose calculations. \t\t\t\t\t\t\t", "The dose selector of your TOUJEO Max SoloStar pen dials by 2 units and can only dial even doses of insulin." ], "text": "" }

{ "type": "", "children": [], "text": "" }

How to read the dose window

{ "type": "p", "children": [], "text": "\nHow to read the dose window\n" }

The dose selector dials by 2 units.

{ "type": "p", "children": [], "text": "The dose selector dials by 2 units." }

Each line in the dose window is an even number.

{ "type": "p", "children": [], "text": "Each line in the dose window is an even number." }

                        60 units selected

{ "type": "p", "children": [], "text": "          \t\t\t\t\t\t\t              60 units selected\n" }

                        58 units selected

{ "type": "p", "children": [], "text": "          \t\t\t\t\t\t\t              58 units selected\n" }

Units of insulin in your pen

{ "type": "p", "children": [], "text": "\nUnits of insulin in your pen\n" }

{ "type": "ul", "children": [ "Your pen contains a total of 900 units of insulin. You can select doses from 2 to 160 units. The dose is adjusted by 2 units at a time. Each pen contains more than 1 dose.", "You can see roughly how many units of insulin are left by looking at where the plunger is on the insulin scale." ], "text": "" }

Step 5: Inject your dose

{ "type": "p", "children": [], "text": "\nStep 5: Inject your dose\n" }

If you find it hard to press the injection button in, do not force it as this may break your pen. See the section below for help.

{ "type": "p", "children": [], "text": "If you find it hard to press the injection button in, do not force it as this may break your pen. See the section below for help." }

{ "type": "", "children": [], "text": "" }

If you find it hard to press the injection button in:

{ "type": "p", "children": [], "text": "\nIf you find it hard to press the injection button in:\n" }

{ "type": "ul", "children": [ "Change the needle (see Step 6 and Step 2) then do a safety test (see Step 3).", "If you still find it hard to press in, get a new pen.", "\nDo not use a syringe to remove insulin from your pen." ], "text": "" }

Step 6: Remove the needle

{ "type": "p", "children": [], "text": "\nStep 6: Remove the needle\n" }

{ "type": "ul", "children": [ "Take care when handling needles to prevent needle injury and cross-infection.", "\nDo not put the inner needle cap back on." ], "text": "" }

{ "type": "", "children": [], "text": "" }

Use by

{ "type": "p", "children": [], "text": "\nUse by\n" }

{ "type": "ul", "children": [ "Only use your pen for up to 56 days after its first use." ], "text": "" }

How to store your pen

{ "type": "p", "children": [], "text": "\nHow to store your pen\n" }

Before first use

{ "type": "p", "children": [], "text": "\nBefore first use\n" }

{ "type": "ul", "children": [ "Keep new pens in the refrigerator between 36°F and 46°F (2°C and 8°C).", "\nDo not freeze. Throw away your pen if it has been frozen (see \t\t\t\t\t\t\t\t\t\"Throwing your pen away\")." ], "text": "" }

After first use

{ "type": "p", "children": [], "text": "\nAfter first use\n" }

{ "type": "ul", "children": [ "Keep your pen at room temperature up to 86°F (30°C).", "Protect your pen from direct heat and light.", "\nDo not put your pen back in the refrigerator.", "\nDo not store your pen with the needle attached.", "Store your pen with the pen cap on.", "Keep TOUJEO Max SoloStar pens and needles out of the reach of children." ], "text": "" }

How to care for your pen

{ "type": "p", "children": [], "text": "\nHow to care for your pen\n" }

Handle your pen with care

{ "type": "p", "children": [], "text": "\nHandle your pen with care\n" }

{ "type": "ul", "children": [ "\nDo not drop your pen or knock it against hard surfaces.", "If you think that your pen may be damaged, do not try to fix it. Use a new one." ], "text": "" }

Protect your pen from dust and dirt

{ "type": "p", "children": [], "text": "\nProtect your pen from dust and dirt\n" }

{ "type": "ul", "children": [ "You can clean the outside of your pen by wiping it with a damp cloth (water only). Do not soak, wash or lubricate your pen. This may damage it." ], "text": "" }

Throwing your pen away

{ "type": "p", "children": [], "text": "\nThrowing your pen away\n" }

{ "type": "ul", "children": [ "The used TOUJEO Max SoloStar pen may be thrown away in your household trash after you have removed the needle.", "Put the used needle in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) needles in your household trash.", "If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:\n–\nmade of a heavy-duty plastic,\n–\ncan be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,\n–\nupright and stable during use,\n–\nleak-resistant, and\n–\nproperly labeled to warn of hazardous waste inside the container.\n\n", "When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at:http://www.fda.gov/safesharpsdisposal.", "\nDo 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." ], "text": "" }

Manufactured by:sanofi-aventis U.S. LLCMorristown, NJ 07960A SANOFI COMPANYU.S. License No. 1752

{ "type": "p", "children": [], "text": "Manufactured by:sanofi-aventis U.S. LLCMorristown, NJ 07960A SANOFI COMPANYU.S. License No. 1752" }

©2025 sanofi-aventis U.S. LLC

{ "type": "p", "children": [], "text": "©2025 sanofi-aventis U.S. LLC" }

TOUJEO and TOUJEO Max SoloStar are registered trademarks of sanofi-aventis U.S. LLC.

{ "type": "p", "children": [], "text": "TOUJEO and TOUJEO Max SoloStar are registered trademarks of sanofi-aventis U.S. LLC." }

Other brands listed are the registered trademarks of their respective owners and are not trademarks of sanofi-aventis U.S. LLC.

{ "type": "p", "children": [], "text": "Other brands listed are the registered trademarks of their respective owners and are not trademarks of sanofi-aventis U.S. LLC." }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration." }

Revised: May 2025

{ "type": "p", "children": [], "text": "Revised: May 2025" }

NDC 0024-5869-03Rx only

{ "type": "p", "children": [], "text": "NDC 0024-5869-03Rx only" }

Toujeo® SoloStar® (insulin glargine) injection

{ "type": "p", "children": [], "text": "Toujeo® SoloStar®\n(insulin glargine) injection" }

For Single Patient Use Only

{ "type": "p", "children": [], "text": "For Single Patient Use Only " }

300 units/mL (U-300)

{ "type": "p", "children": [], "text": "300 units/mL (U-300)" }

For subcutaneous use only Solution for injection in a disposable insulin delivery device Do not remove insulin with syringe Always use a new needle – Do not mix with other insulins Use only if solution is clear and colorless with no particles visible

{ "type": "p", "children": [], "text": "For subcutaneous use only Solution for injection in a disposable insulin delivery device Do not remove insulin with syringe Always use a new needle – Do not mix with other insulins Use only if solution is clear and colorless with no particles visible" }

Use within 56 days after opening *Needles not included (see back panel) Three 1.5 mL prefilled pens – Dispense in this sealed carton

{ "type": "p", "children": [], "text": "Use within 56 days after opening *Needles not included (see back panel) Three 1.5 mL prefilled pens – Dispense in this sealed carton" }

sanofi

{ "type": "p", "children": [], "text": "sanofi" }

NDC 0024-5871-02Rx only

{ "type": "p", "children": [], "text": "NDC 0024-5871-02Rx only" }

Toujeo Max SoloStar® (insulin glargine) injection

{ "type": "p", "children": [], "text": "Toujeo Max SoloStar®\n(insulin glargine) injection" }

For Single Patient Use Only

{ "type": "p", "children": [], "text": "For Single Patient Use Only " }

300 units/mL (U-300) Adjusts by 2 units

{ "type": "p", "children": [], "text": "300 units/mL (U-300) Adjusts by 2 units" }

For subcutaneous use only Solution for injection in a disposable insulin delivery device Do not remove insulin with syringe Always use a new needle – Do not mix with other insulins Use only if solution is clear and colorless with no particles visible

{ "type": "p", "children": [], "text": "For subcutaneous use only Solution for injection in a disposable insulin delivery device Do not remove insulin with syringe Always use a new needle – Do not mix with other insulins Use only if solution is clear and colorless with no particles visible" }

Use within 56 days after opening *Needles not included (see back panel) Two 3 mL prefilled pens – Dispense in this sealed carton

{ "type": "p", "children": [], "text": "Use within 56 days after opening *Needles not included (see back panel) Two 3 mL prefilled pens – Dispense in this sealed carton" }

sanofi

{ "type": "p", "children": [], "text": "sanofi" }