Long-Acting Insulins

Initial U.S. Approval:  2015

Mechanism of Action: The primary activity of insulin, including TRESIBA, 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 also inhibits lipolysis and proteolysis, and enhances protein synthesis. TRESIBA forms multi-hexamers when injected into the subcutaneous tissue resulting in a subcutaneous insulin degludec depot. The protracted time action profile of TRESIBA is predominantly due to delayed absorption of insulin degludec from the subcutaneous tissue to the systemic circulation and to a lesser extent due to binding of insulin-degludec to circulating albumin.

INDICATIONS AND USAGE:  TRESIBA is indicated to improve glycemic control in adults with diabetes mellitus.

Limitations of Use
TRESIBA is not recommended for the treatment of diabetic ketoacidosis.

Dosing:
Individualize dose based on type of diabetes, metabolic needs, blood glucose monitoring results and glycemic control goal.
Rotate injection sites to reduce the risk of lipodystrophy.
Do not dilute or mix with any other insulin or solution.
Administer subcutaneously once daily at any time of day.
Do NOT perform dose conversion when using the TRESIBA U-100 or U-200 FlexTouch pens. The TRESIBA U-100 and U-200 FlexTouch pens dose window shows the number of insulin units to be delivered and NO conversion is needed.

HOW SUPPLIED:
TRESIBA is available as a clear, and colorless solution for injection in:

100 units/mL (U-100): 3 mL FlexTouch disposable prefilled pen
200 units/mL (U-200): 3 mL FlexTouch disposable prefilled pen

CLINICAL PHARMACOLOGY
Mechanism of Action
The primary activity of insulin detemir is the regulation of glucose metabolism. Insulins, including insulin detemir, exert their specific action through binding to insulin receptors.

Receptor-bound insulin lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and fat and by inhibiting the output of glucose from the liver. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis.

Pharmacodynamics
Insulin detemir is a soluble, long-acting basal human insulin analog with a relatively flat action profile. The mean duration of action of insulin detemir ranged from 5.7 hours at the lowest dose to 23.2 hours at the highest dose (sampling period 24 hours).

The prolonged action of LEVEMIR is mediated by the slow systemic absorption of insulin detemir molecules from the injection site due to strong self-association of the drug molecules and albumin binding. Insulin detemir is distributed more slowly to peripheral target tissues since insulin detemir in the bloodstream is highly bound to albumin.

For doses in the interval of 0.2 to 0.4 U/kg, LEVEMIR exerts more than 50% of its maximum effect from 3 to 4 hours up to approximately 14 hours after dose administration.

Pharmacokinetics   ----------------------------------
Absorption
After subcutaneous injection of insulin detemir in healthy subjects and in patients with diabetes, insulin detemir serum concentrations indicated a slower, more prolonged absorption over 24 hours in comparison to NPH human insulin.

Maximum serum concentration (Cmax) is reached between 6 and 8 hours after administration.
The absolute bioavailability of insulin detemir is approximately 60%.

Distribution and Elimination
More than 98% insulin detemir in the bloodstream is bound to albumin. LEVEMIR has a small apparent volume of distribution of approximately 0.1 L/kg. LEVEMIR, after subcutaneous administration, has a terminal half-life of 5 to7 hours depending on dose.

Special Populations
Children and Adolescents- The pharmacokinetic properties of LEVEMIR were investigated in children (6 to 12 years) and adolescents (13 to 17 years) and adults with type 1 diabetes. Similar to NPH human insulin, slightly higher plasma Area Under the Curve (AUC) and Cmax were observed in children by 10% and 24%, respectively, compared to adolescents and adults. There was no difference in pharmacokinetics between adolescents and adults.

Geriatrics- In a clinical trial investigating differences in pharmacokinetics of a single subcutaneous dose of LEVEMIR in young (25 to 35 years) versus elderly (≥68 years) healthy subjects, higher insulin AUC levels (up to 35%) were found in elderly subjects due to a reduced clearance. As with other insulin preparations, LEVEMIR should always be titrated according to individual requirements.

Gender- In controlled clinical trials, no clinically relevant difference between genders is seen in pharmacokinetic parameters based on subgroup analyses.

Race- In two trials in healthy Japanese and Caucasian subjects, there were no clinically relevant differences seen in pharmacokinetic parameters. Pharmacokinetics and pharmacodynamics of LEVEMIR were investigated in a clamp trial comparing patients with type 2 diabetes of Caucasian, African-American, and Latino origin. Dose-response relationships were comparable for LEVEMIR in these three populations.

Renal impairment- Individuals with renal impairment showed no difference in pharmacokinetic parameters as compared to healthy volunteers. However, literature reports have shown that clearance of human insulin is decreased in renally impaired patients. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with renal dysfunction (see PRECAUTIONS, Renal Impairment).

Hepatic impairment- Individuals with severe hepatic dysfunction, without diabetes, were observed to have lower AUCs as compared to healthy volunteers. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR, may be necessary in patients with hepatic dysfunction (see PRECAUTIONS, Hepatic Impairment).

Pregnancy- The effect of pregnancy on the pharmacokinetics and pharmacodynamics of LEVEMIR has not been studied (see package insert: PRECAUTIONS, Pregnancy ).

Smoking- The effect of smoking on the pharmacokinetics and pharmacodynamics of LEVEMIR has not been studied

INDICATIONS AND USAGE
LEVEMIR is indicated for once- or twice-daily subcutaneous administration for the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal (long acting) insulin for the control of hyperglycemia.

CONTRAINDICATIONS
LEVEMIR is contraindicated in patients hypersensitive to insulin detemir or one of its excipients.

WARNINGS
Hypoglycemia is the most common adverse effect of insulin therapy, including LEVEMIR. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations.

Glucose monitoring is recommended for all patients with diabetes.

LEVEMIR is not to be used in insulin infusion pumps.

Any change of insulin dose should be made cautiously and only under medical supervision. Changes in insulin strength, timing of dosing, manufacturer, type (e.g., regular, NPH, or insulin analogs), species (animal, human), or method of manufacture (rDNA versus animal-source insulin) may result in the need for a change in dosage.

Concomitant oral antidiabetic treatment may need to be adjusted.

Needles and Levemir FlexPen must not be shared

PRECAUTIONS
General
Inadequate dosing or discontinuation of treatment may lead to hyperglycemia and, in patients with type 1 diabetes, diabetic ketoacidosis. The first symptoms of hyperglycemia usually occur gradually over a period of hours or days. They include nausea, vomiting, drowsiness, flushed dry skin, dry mouth, increased urination, thirst and loss of appetite as well as acetone breath. Untreated hyperglycemic events are potentially fatal.

LEVEMIR is not intended for intravenous or intramuscular administration. The prolonged duration of activity of insulin detemir is dependent on injection into subcutaneous tissue. Intravenous administration of the usual subcutaneous dose could result in severe hypoglycemia. Absorption after intramuscular administration is both faster and more extensive than absorption after subcutaneous administration.

LEVEMIR should not be diluted or mixed with any other insulin preparations

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

Lipodystrophy and hypersensitivity are among potential clinical adverse effects associated with the use of all insulins.

As with all insulin preparations, the time course of LEVEMIR action may vary in different individuals or at different times in the same individual and is dependent on site of injection, blood supply, temperature, and physical activity.

Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan.

Hypoglycemia
As with all insulin preparations, hypoglycemic reactions may be associated with the administration of LEVEMIR. Hypoglycemia is the most common adverse effect of insulins. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or intensified diabetes control (see PRECAUTIONS, Drug Interactions). Such situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to patients’ awareness of hypoglycemia.

The time of occurrence of hypoglycemia depends on the action profile of the insulins used and may, therefore, change when the treatment regimen or timing of dosing is changed. In patients being switched from other intermediate or long-acting insulin preparations to once- or twice-daily LEVEMIR, dosages can be prescribed on a unit-to-unit basis; however, as with all insulin preparations, dose and timing of administration may need to be adjusted to reduce the risk of hypoglycemia (see DOSAGE AND ADMINISTRATION, Changeover to LEVEMIR).

Renal Impairment
As with other insulins, the requirements for LEVEMIR may need to be adjusted in patients with renal impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

Hepatic Impairment
As with other insulins, the requirements for LEVEMIR may need to be adjusted in patients with hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

Injection Site and Allergic Reactions
As with any insulin therapy, lipodystrophy may occur at the injection site and delay insulin absorption. Other injection site reactions with insulin therapy may include redness, pain, itching, hives, swelling, and inflammation. Continuous rotation of the injection site within a given area may help to reduce or prevent these reactions. Reactions usually resolve in a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of LEVEMIR.

In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique.

Systemic allergy: Generalized allergy to insulin, which is less common but potentially more serious, may cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic reaction, may be life-threatening.

Intercurrent Conditions
Insulin requirements may be altered during intercurrent conditions such as illness, emotional disturbances, or other stresses

Laboratory Tests
As with all insulin therapy, the therapeutic response to LEVEMIR should be monitored by periodic blood glucose tests. Periodic measurement of HbA1c is recommended for the monitoring of long-term glycemic control.

Drug Interactions
A number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring.

The following are examples of substances that may reduce the blood-glucose-lowering effect of insulin: corticosteroids, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline), isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives).

The following are examples of substances that may increase the blood-glucose-lowering effect of insulin and susceptibility to hypoglycemia: oral antidiabetic drugs, ACE inhibitors, disopyramide, fibrates, fluoxetine, MAO inhibitors, propoxyphene, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics.

Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. In addition, under the influence of sympatholytic medicinal products such as beta-blockers, clonidine, guanethidine, and reserpine, the signs of hypoglycemia may be reduced or absent.

The results of in-vitro and in-vivo protein binding studies demonstrate that there is no clinically relevant interaction between insulin detemir and fatty acids or other protein bound drugs.

Mixing of Insulins
If LEVEMIR is mixed with other insulin preparations, the profile of action of one or both individual components may change. Mixing LEVEMIR with insulin aspart, a rapid acting insulin analog, resulted in about 40% reduction in AUC(0-2h) and Cmax for insulin aspart compared to separate injections when the ratio of insulin aspart to LEVEMIR was less than 50%.

LEVEMIR should NOT be mixed or diluted with any other insulin preparations.

Pregnancy
Preganancy Category C

Teratogenic effects
In a fertility and embryonic development study, insulin detemir was administered to female rats before mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times the recommended human dose, based on plasma Area Under the Curve (AUC) ratio). Doses of 150 and 300 nmol/kg/day produced numbers of litters with visceral anomalies. Doses up to 900 nmol/kg/day (approximately 135 times the recommended human dose based on AUC ratio) were given to rabbits during organogenesis. Drug-dose related increases in the incidence of fetuses with gall bladder abnormalities such as small, bilobed, bifurcated and missing gall bladders were observed at a dose of 900 nmol/kg/day. The rat and rabbit embryofetal development studies that included concurrent human insulin control groups indicated that insulin detemir and human insulin had similar effects regarding embryotoxicity and teratogenicity.

Nursing mothers
It is unknown whether LEVEMIR is excreted in significant amounts in human milk. For this reason, caution should be exercised when LEVEMIR is administered to a nursing mother. Patients with diabetes who are lactating may require adjustments in insulin dose, meal plan, or both.

Pediatric use
In a controlled clinical study, HbA1c concentrations and rates of hypoglycemia were similar among patients treated with LEVEMIR and patients treated with NPH human insulin.

Geriatric use
Of the total number of subjects in intermediate and long-term clinical studies of LEVEMIR, 85 (type 1 studies) and 363 (type 2 studies) were 65 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly.

DOSAGE AND ADMINISTRATION
LEVEMIR can be administered once- or twice-daily. The dose of LEVEMIR should be adjusted according to blood glucose measurements. The dosage of LEVEMIR should be individualized based on the physician’s advice, in accordance with the needs of the patient

• For patients treated with Levemir once-daily, the dose should be administered with the evening meal or at bedtime.
• For patients who require twice-daily dosing for effective blood glucose control, the evening dose can be administered either with the evening meal, at bedtime, or 12 hours after the morning dose.

LEVEMIR should be administered by subcutaneous injection in the thigh, abdominal wall, or upper arm. Injection sites should be rotated within the same region. As with all insulins, the duration of action will vary according to the dose, injection site, blood flow, temperature, and level of physical activity.

Dose Determination for LEVEMIR

• For patients with type 1 or type 2 diabetes on basal-bolus treatment, changing the basal insulin to LEVEMIR can be done on a unit-to-unit basis. The dose of LEVEMIR should then be adjusted to achieve glycemic targets. In some patients with type 2 diabetes, more LEVEMIR may be required than NPH insulin. In a clinical study, the mean dose at end of treatment was 0.77 U/kg for LEVEMIR and 0.52 IU/kg for NPH human insulin (see Table 3).
• For patients currently receiving only basal insulin, changing the basal insulin to LEVEMIR can be done on a unit-to-unit basis.
• For insulin-naïve patients with type 2 diabetes who are inadequately controlled on oral antidiabetic drugs, LEVEMIR should be started at a dose of 0.1 to 0.2 U/kg once-daily in the evening or 10 units once- or twice-daily, and the dose adjusted to achieve glycemic targets.
• As with all insulins, close glucose monitoring is recommended during the transition and in the initial weeks thereafter. Dose and timing of concurrent short-acting insulins or other concomitant antidiabetic treatment may need to be adjusted.

Preparation and Handling
LEVEMIR should be inspected visually prior to administration and should only be used if the solution appears clear and colorless.

LEVEMIR should not be mixed or diluted with any other insulin preparations.

After each injection, patients must remove the needle without recapping and dispose of it in a puncture-resistant container. Used syringes, needles, or lancets should be placed in “sharps” containers (such as red biohazard containers), hard plastic containers (such as detergent bottles), or metal containers (such as an empty coffee can). Such containers should be sealed and disposed of properly.

HOW SUPPLIED
LEVEMIR is available in the following package sizes: each presentation containing 100 Units of insulin detemir per mL (U-100).

*LEVEMIR PenFill® cartridges are for use with Novo Nordisk 3 mL PenFill® cartridge compatible insulin delivery devices and NovoFine® disposable needles.

RECOMMENDED STORAGE
Unused LEVEMIR should be stored between 2° and 8°C (36° to 46° F). Do not freeze. Do not use LEVEMIR if it has been frozen.

Vials:

After initial use, vials should be stored in a refrigerator, never in a freezer. If refrigeration is not possible, the in-use vial can be kept unrefrigerated at room temperature, below 30°C (86°F), for up to 42 days, as long as it is kept as cool as possible and away from direct heat and light.

Unpunctured vials can be used until the expiration date printed on the label if they are stored in a refrigerator. Keep unused vials in the carton so they will stay clean and protected from light.

PenFill® cartridges, FlexPen® or InnoLet®:

After initial use, a cartridge (PenFill®) or a prefilled syringe (including FlexPen® or InnoLet®) may be used for up to 42 days if it is kept at room temperature, below 30°C (86°F). In-use cartridges and prefilled syringes in-use must NOT be stored in a refrigerator and must NOT be stored with the needle in place. Keep all cartridges and prefilled syringes away from direct heat and sunlight.

Not in-use (unopened) LEVEMIR PenFill®, FlexPen® or InnoLet® can be used until the expiration date printed on the label if they are stored in a refrigerator. Keep unused cartridges and prefilled syringes in the carton so they will stay clean and protected from light.

The storage conditions are summarized in the following table:

INDICATIONS AND USAGE
LANTUS is a long- acting human insulin analog indicated to improve glycemic control in adults and children with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus.

Important Limitations of Use:
Not recommended for treating diabetic ketoacidosis. Use intravenous, short-acting insulin instead.

Clinical Pharmacology (Below).

DOSAGE AND ADMINISTRATION

• The starting dose should be individualized based on the type of diabetes and whether the patient is insulin-naïve
• Administer subcutaneously once daily at any time of day, but at the same time every day.
• Rotate injection sites within an injection area (abdomen, thigh, or deltoid) to reduce the risk of lipodystrophy.
• Converting from other insulin therapies may require adjustment of timing and dose of LANTUS. Closely monitor glucoses especially upon converting to LANTUS and during the initial weeks thereafter.
• Further information.

DOSAGE FORMS AND STRENGTHS
Solution for injection 100 units/mL (U-100) in

• 10 mL vials
• 3 mL cartridge system for use in OptiClik (Insulin Delivery Device)
• 3 mL SoloStar disposable insulin device

CONTRAINDICATIONS
Do not use in patients with hypersensitivity to LANTUS or one of its excipients.

WARNINGS AND PRECAUTIONS

• Dose adjustment and monitoring: Monitor blood glucose in all patients treated with insulin. Insulin regimens should be modified cautiously and only under medical supervision.
• Administration: Do not dilute or mix with any other insulin or solution. Do not administer subcutaneously via an insulin pump or intravenously because severe hypoglycemia can occur.
• Do not share reusable or disposable insulin devices or needles between patients.
• Hypoglycemia: Most common adverse reaction of insulin therapy and may be life-threatening.
• Allergic reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur.
• Renal or hepatic impairment: May require a reduction in the LANTUS dose.
• Further information

ADVERSE REACTIONS
Adverse reactions commonly associated with Lantus are:
Hypoglycemia, allergic reactions, injection site reaction, lipodystrophy, pruritus, and rash.

To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

• Certain drugs may affect glucose metabolism, requiring insulin dose adjustment and close monitoring of blood glucose.
• The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine).
• Further information

USE IN SPECIFIC POPULATIONS

• Pregnancy category C: Use during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• Pediatric: Has not been studied in children with type 2 diabetes. Has not been studied in children with type 1 diabetes <6 years of age.

HOW SUPPLIED/STORAGE AND HANDLING

DOSAGE AND ADMINISTRATION (FULL PRESCRIBING)

Dosing
LANTUS is a recombinant human insulin analog for once daily subcutaneous administration with potency that is approximately the same as the potency of human insulin. LANTUS exhibits a relatively constant glucose-lowering profile over 24 hours that permits once-daily dosing.

LANTUS may be administered at any time during the day. LANTUS should be administered subcutaneously once a day at the same time every day. The dose of LANTUS must be individualized based on clinical response. Blood glucose monitoring is essential in all patients receiving insulin therapy.

Patients adjusting the amount or timing of dosing with LANTUS, should only do so under medical supervision with appropriate glucose monitoring.

In patients with type 1 diabetes, LANTUS must be used in regimens with short-acting insulin.

The intended duration of activity of LANTUS is dependent on injection into subcutaneous tissue. LANTUS should not be administered intravenously or via an insulin pump. Intravenous administration of the usual subcutaneous dose could result in severe hypoglycemia.

As with all insulins, injection sites should be rotated within the same region (abdomen, thigh, or deltoid) from one injection to the next to reduce the risk of lipodystrophy.

In clinical studies, there was no clinically relevant difference in insulin glargine absorption after abdominal, deltoid, or thigh subcutaneous administration. As for all insulins, the rate of absorption, and consequently the onset and duration of action, may be affected by exercise and other variables, such as stress, intercurrent illness, or changes in co-administered drugs or meal patterns.

Initiation of LANTUS therapy
The recommended starting dose of LANTUS in patients with type 1 diabetes should be approximately one-third of the total daily insulin requirements. Short-acting, premeal insulin should be used to satisfy the remainder of the daily insulin requirements.

The recommended starting dose of LANTUS in patients with type 2 diabetes who are not currently treated with insulin is 10 units (or 0.2 Units/kg) once daily, which should subsequently be adjusted to the patient's needs.

The dose of LANTUS should be adjusted according to blood glucose measurements. The dosage of LANTUS should be individualized under the supervision of a healthcare provider in accordance with the needs of the patient.

Converting to LANTUS from other insulin therapies
If changing from a treatment regimen with an intermediate- or long-acting insulin to a regimen with LANTUS, the amount and timing of shorter-acting insulins and doses of any oral anti-diabetic drugs may need to be adjusted.

If transferring patients from once-daily NPH insulin to once-daily LANTUS, the recommended initial LANTUS dose is the same as the dose of NPH that is being discontinued.
If transferring patients from twice-daily NPH insulin to once-daily LANTUS, the recommended initial LANTUS dose is 80% of the total NPH dose that is being discontinued. This dose reduction will lower the likelihood of hypoglycemia.

WARNINGS AND PRECAUTIONS
Dosage adjustment and monitoring
Glucose monitoring is essential for all patients receiving insulin therapy. Changes to an insulin regimen should be made cautiously and only under medical supervision.

Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a change in insulin dose or an adjustment in concomitant oral anti-diabetic treatment.

As with all insulin preparations, the time course of action for LANTUS may vary in different individuals or at different times in the same individual and is dependent on many conditions, including the local blood supply, local temperature, and physical activity.

Administration
Do not administer LANTUS intravenously or via an insulin pump. The intended duration of activity of LANTUS is dependent on injection into subcutaneous tissue

Intravenous administration of the usual subcutaneous dose could result in severe hypoglycemia
Do not dilute or mix LANTUS with any other insulin or solution. If LANTUS is diluted or mixed, the solution may become cloudy, and the pharmacokinetic or pharmacodynamic profile (e.g., onset of action, time to peak effect) of LANTUS and the mixed insulin may be altered in an unpredictable manner. When LANTUS and regular human insulin were mixed immediately before injection in dogs, a delayed onset of action and a delayed time to maximum effect for regular human insulin was observed. The total bioavailability of the mixture was also slightly decreased compared to separate injections of LANTUS and regular human insulin. The relevance of these observations in dogs to humans is unknown.

Do not share disposable or reusable insulin devices or needles between patients, because doing so carries a risk for transmission of blood-borne pathogens.

Hypoglycemia
Hypoglycemia is the most common adverse reaction of insulin, including LANTUS. The risk of hypoglycemia increases with intensive glycemic control. Patients must be educated to recognize and manage hypoglycemia. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person or parenteral glucose infusion or glucagon administration has been observed in clinical trials with insulin, including trials with LANTUS.

The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals), exercise, and concomitant medications may also alter the risk of hypoglycemia

Hypersensitivity and allergic reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including LANTUS.

Renal impairment
Due to its long duration of action, Lantus is not recommended during periods of rapidly declining renal function because of the risk for prolonged hypoglycemia.

Although studies have not been performed in patients with diabetes and renal impairment, a reduction in the LANTUS dose may be required in patients with renal impairment because of reduced insulin metabolism, similar to observations found with other insulins. [See Clinical Pharmacology (12.3)].

Hepatic impairment
Due to its long duration of action, Lantus is not recommended during periods of rapidly declining hepatic function because of the risk for prolonged hypoglycemia.

Although studies have not been performed in patients with diabetes and hepatic impairment, a reduction in the LANTUS dose may be required in patients with hepatic impairment because of reduced capacity for gluconeogenesis and reduced insulin metabolism, similar to observations found with other insulins.

DRUG INTERACTIONS
A number of drugs affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring.

The following are examples of drugs that may increase the blood-glucose-lowering effect of insulins including LANTUS and, therefore, increase the susceptibility to hypoglycemia: oral anti-diabetic products, pramlintide, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, propoxyphene, pentoxifylline, salicylates, somatostatin analogs, and sulfonamide antibiotics.

The following are examples of drugs that may reduce the blood-glucose-lowering effect of insulins including LANTUS: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline), glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives), protease inhibitors and atypical antipsychotic medications (e.g. olanzapine and clozapine).

Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.

The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine.

USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C: 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 7 times the recommended human subcutaneous starting dose of 10 Units/day (0.008 mg/kg/day), based on mg/m2. In rabbits, doses of 0.072 mg/kg/day, which is approximately 2 times the recommended human subcutaneous starting dose of 10 Units/day (0.008 mg/kg/day), based on mg/m2, 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.

There are no well-controlled clinical studies of the use of LANTUS in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is essential for patients with diabetes or a history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is essential in these patients.

Nursing Mothers
It is unknown whether insulin glargine is excreted in human milk. Because many drugs, including human insulin, are excreted in human milk, caution should be exercised when LANTUS is administered to a nursing woman. Use of LANTUS is compatible with breastfeeding, but women with diabetes who are lactating may require adjustments of their insulin doses.

Pediatric Use
The safety and effectiveness of subcutaneous injections of LANTUS have been established in pediatric patients (age 6 to 15 years) with type 1 diabetes [see Clinical Studies (14)]. LANTUS has not been studied in pediatric patients younger than 6 years of age with type 1 diabetes. LANTUS has not been studied in pediatric patients with type 2 diabetes.

Based on the results of a study in pediatric patients, the dose recommendation when switching to LANTUS is the same as that described for adults [see Dosage and Administration (2.3) and Clinical Studies (14)]. As in adults, the dosage of LANTUS must be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood glucose.

Geriatric Use
In controlled clinical studies comparing LANTUS to NPH insulin, 593 of 3890 patients (15%) with type 1 and type 2 diabetes were ≥65 years of age and 80 (2%) patients were ≥75 years of age. The only difference in safety or effectiveness in the subpopulation of patients ≥65 years of age compared to the entire study population was a higher incidence of cardiovascular events typically seen in an older population in both LANTUS and NPH insulin-treated patients.

Nevertheless, caution should be exercised when LANTUS is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly

CLINICAL PHARMACOLOGY
Mechanism of Action
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.

Pharmacodynamics
Insulin glargine is a human insulin analog that has been designed to have low aqueous solubility at neutral pH. At pH 4, as in the LANTUS injection solution, insulin glargine is completely soluble. After injection into the subcutaneous tissue, the acidic solution is neutralized, leading to formation of microprecipitates from which small amounts of insulin glargine are slowly released, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peak. This profile allows once-daily dosing as a basal insulin.

In clinical studies, the glucose-lowering effect on a molar basis (i.e., when given at the same doses) of intravenous insulin glargine is approximately the same as that for human insulin. In euglycemic clamp studies in healthy subjects or in patients with type 1 diabetes, the onset of action of subcutaneous insulin glargine was slower than NPH insulin. The effect profile of insulin glargine was relatively constant with no pronounced peak and the duration of its effect was prolonged compared to NPH insulin. The median time between injection and the end of pharmacological effect was 14.5 hours (range: 9.5 to 19.3 hours) for NPH insulin, and 24 hours (range: 10.8 to >24.0 hours) (24 hours was the end of the observation period) for insulin glargine.

The longer duration of action (up to 24 hours) of LANTUS is directly related to its slower rate of absorption and supports once-daily subcutaneous administration. The time course of action of insulins, including LANTUS, may vary between individuals and within the same individual.

Pharmacokinetics
Absorption and Bioavailability. After subcutaneous injection of insulin glargine in healthy subjects and in patients with diabetes, the insulin serum concentrations indicated a slower, more prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak in comparison to NPH insulin. Serum insulin concentrations were thus consistent with the time profile of the pharmacodynamic activity of insulin glargine.

After subcutaneous injection of 0.3 Units/kg insulin glargine in patients with type 1 diabetes, a relatively constant concentration/time profile has been demonstrated. The duration of action after abdominal, deltoid, or thigh subcutaneous administration was similar.

Metabolism. A metabolism study in humans indicates that insulin glargine is partly metabolized at the carboxyl terminus of the B chain in the subcutaneous depot to form two active metabolites with in vitro activity similar to that of insulin, M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin). Unchanged drug and these degradation products are also present in the circulation.

Special Populations
Age, Race, and Gender. Information on the effect of age, race, and gender on the pharmacokinetics of LANTUS is not available. However, in controlled clinical trials in adults (n=3890) and a controlled clinical trial in pediatric patients (n=349), subgroup analyses based on age, race, and gender did not show differences in safety and efficacy between insulin glargine and NPH insulin.

Smoking. The effect of smoking on the pharmacokinetics/pharmacodynamics of LANTUS has not been studied.

Pregnancy. The effect of pregnancy on the pharmacokinetics and pharmacodynamics of LANTUS has not been studied.

Obesity. In controlled clinical trials, which included patients with Body Mass Index (BMI) up to and including 49.6 kg/m2, subgroup analyses based on BMI did not show differences in safety and efficacy between insulin glargine and NPH insulin.

Renal Impairment. The effect of renal impairment on the pharmacokinetics of LANTUS has not been studied. However, some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. Careful glucose monitoring and dose adjustments of insulin, including LANTUS, may be necessary in patients with renal impairment.

Hepatic Impairment. The effect of hepatic impairment on the pharmacokinetics of LANTUS has not been studied. However, some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure. Careful glucose monitoring and dose adjustments of insulin, including LANTUS, may be necessary in patients with hepatic impairment

HOW SUPPLIED/STORAGE AND HANDLING
How supplied
LANTUS solution for injection 100 units per mL (U-100) is available as:

Needles are not included in the packs.

BD Ultra-Fine™ needles¹ to be used in conjunction with SoloStar and OptiClik are sold separately and are manufactured by BD.
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1 .  The brands listed are the registered trademarks of their respective owners and are not trademarks of sanofi-aventis U.S. LLC

Storage------------------------------------------
LANTUS should not be stored in the freezer and should not be allowed to freeze. Discard LANTUS if it has been frozen.

Unopened Vial/Cartridge system/SoloStar disposable insulin device:
Unopened LANTUS vials, cartridge systems and SoloStar device should be stored in a refrigerator, 36°F – 46°F (2°C – 8°C). Discard after the expiration date.

Open (In-Use) Vial:
Vials must be discarded 28 days after being opened. If refrigeration is not possible, the open vial can be kept unrefrigerated for up to 28 days away from direct heat and light, as long as the temperature is not greater than 86°F (30°C).

Open (In-Use) Cartridge system:
The opened (in-use) cartridge system in OptiClik should NOT be refrigerated but should be kept at room temperature (below 86°F [30°C]) away from direct heat and light. The opened (in-use) cartridge system in OptiClik must be discarded 28 days after being opened. Do not store OptiClik , with or without cartridge system, in a refrigerator at any time.

Open (In-Use) SoloStar disposable insulin device:
The opened (in-use) SoloStar should NOT be refrigerated but should be kept at room temperature (below 86°F [30°C]) away from direct heat and light. The opened (in-use) SoloStar device must be discarded 28 days after being opened.

These storage conditions are summarized in the following table: