LANTUS(r) [insulin glargine injection (rDNA origin)] is a recombinant human insulin analogue that is a long-acting, parenteral blood-glucose-lowering agent. LANTUS(r) is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12) as the production organism.

Insulin glargine differs from natural human insulin in that the amino acid asparagine at position 21 of the A-chain is replaced by glycine and two arginines are added to the C-terminus of the B- chain (See PHARMACEUTICAL INFORMATION, Drug Substance).

CONTRAINDICATIONS

LANTUS(r) [insulin glargine injection (rDNA origin)] is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.

WARNINGS AND PRECAUTIONS

Hypoglycemia is the most common adverse effect of insulin, including LANTUS(r). As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose monitoring is recommended for all patients with diabetes.

Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin strength, timing of administration, manufacturer, type (e.g., regular, NPH, or insulin analogs), species (animal, human), or method of manufacture (recombinant DNA versus animal- source insulin) may result in the need for a change in dosage. Concomitant oral antidiabetic treatment may need to be adjusted. As with all insulins, when transferring to LANTUS(r), the early warning symptoms of hypoglycemia may be changed, be less pronounced, or absent. The prolonged effect of subcutaneous LANTUS(r) may delay recovery from hypoglycemia.

LANTUS(r) must not be mixed with any other insulin or diluted with any other solution (See DOSAGE AND ADMINISTRATION: Administration). If LANTUS(r) is diluted or mixed, the solution may become cloudy, and the pharmacokinetic/ pharmacodynamic profile (e.g., onset of action, time to peak effect) of LANTUS(r) and/or the mixed insulin may be altered in an unpredictable manner. When LANTUS(r) and regular human insulin were mixed immediately before injection in dogs, a delayed onset of action and 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(r) and regular human insulin. The relevance of these observations in dogs to humans is not known.

LANTUS(r) [insulin glargine injection (rDNA origin)] is not intended for intravenous or intramuscular administration. The prolonged duration of activity of insulin glargine is dependent on injection into subcutaneous tissue. Intravenous administration of the usual subcutaneous dose could result in severe hypoglycemia.

Hypoglycemia may occur if the insulin dose is too high in relation to the insulin requirement (see Hypoglycemia section below). The use of too low insulin dosages or discontinuation of treatment, especially in Type 1 diabetes, may lead to hyperglycemia and diabetic ketoacidosis. Uncorrected hypoglycemic or hyperglycemic reactions can cause loss of consciousness, coma, or death.

As with all insulin preparations, the time course of LANTUS(r) action may vary in different individuals or at different times in the same individual and the rate of absorption is dependent on blood supply, temperature, and physical activity.

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

Patients with human insulin antibodies may be hypersensitive to other insulins, with a risk of hypoglycemia and/or cross-reactivity.

Although studies have not been performed in patients with diabetes and hepatic impairment, LANTUS(r) requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism (See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).

As with all insulin preparations, hypoglycemic reaction, especially during initiation of therapy, may be associated with the administration of LANTUS(r). Hypoglycemia is the most common adverse effect of insulins. Early warning symptoms of hypoglycemia may be different, be less pronounced or absent under certain conditions, as for example, in patients whose glycemic control is markedly improved, in elderly patients, in patients where an autonomic neuropathy is present, in patients whose hypoglycemia is developing gradually, in patients with a long history of diabetes, in patients with psychiatric illness, or in patients receiving concurrent treatment with certain other drugs such as beta-blockers. Hypoglycemia may occur with other substances including alcohol and psychiatric medications, street drugs, birth control pills, injections and patches (See DRUG INTERACTIONS: Drug-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 administration is changed.

As with all insulins, additional caution (including intensified blood glucose monitoring) should be exercised in patient populations who are at greater risk for clinically significant sequelae from hypoglycemic episodes.

In a clinical study, symptoms of hypoglycemia or counter regulatory hormone responses were similar after intravenous insulin glargine and regular human insulin both in healthy subjects and adult patients with type 1 diabetes.

Insulin administration may cause insulin antibodies to form. In clinical studies, antibodies that cross-react with human insulin and insulin glargine were observed in both NPH human insulin and insulin glargine treatment groups with similar percents of increased and decreased titers. There was no correlation in either treatment group between increases or decreases in these antibody titers and changes in either A1C or total insulin requirements. In theory, the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyperglycemia or hypoglycemia, but has not been found on review of LANTUS(r) clinical trials and available post-marketing data.

As with any insulin therapy, lipodystrophy may occur at the injection site and delay insulin absorption. Other injection site reactions with insulin therapy 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. Most minor reactions to insulins usually resolve in a few days to a few weeks.

Immediate-type allergic reactions are rare. Such reactions to insulin (including insulin glargine) or the excipients may, for example, be associated with generalized skin reactions, angioedema, bronchospasm, hypotension, or shock and may be life threatening.

Reports of injection site pain were more frequent with LANTUS(r) than NPH human insulin (2.7% insulin glargine versus 0.7% human NPH). The reports of pain at the injection site were usually mild and did not result in discontinuation of therapy. Other possibly related treatment- emergent injection site reactions occurred at similar incidences with both insulin glargine and NPH human insulin.

Insulin requirements may be altered during intercurrent conditions such as infection or illness, emotional disturbances, or stress.

Although studies have not been performed in patients with diabetes and renal impairment, LANTUS(r) requirements may be diminished due to reduced insulin metabolism (See WARNINGS AND PRECAUTIONS, Special Populations). Careful glucose monitoring and dose adjustments of insulin or insulin analogues including LANTUS(r) may be necessary in patients with renal dysfunction.

Pregnant Women:

Teratogenic effects. There are no well-controlled clinical studies of the use of insulin glargine in pregnant women. Only a limited number of pregnancies were exposed during Post Marketing Surveillance with insulin glargine. As with other insulins, adverse pregnancy outcomes did not indicate any trends suggesting a link to insulin glargine. To date, no other relevant epidemiological data are available. 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 such patients. Patients with diabetes should be advised to inform their doctor if they are pregnant or are contemplating pregnancy (Also see Part II: TOXICOLOGY, Reproduction Toxicity and Impairment of Fertility).

Nursing Women:

It is unknown whether insulin glargine is excreted in significant amounts in human milk. Many drugs, including human insulin, are excreted in human milk. For this reason, caution should be exercised when LANTUS(r) is administered to a nursing woman. Lactating women may require adjustments in insulin dose and diet.

Pediatrics (> 6 years of age):

Safety and effectiveness of LANTUS(r) has been established in children over 6 years of age with Type 1 diabetes mellitus. (See ACTIONS AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, and INDICATIONS AND CLINICAL USE).

Geriatrics (> 65 years of age):

In controlled clinical studies comparing insulin glargine to NPH human insulin, 593 of 3890 patients with type 1 and type 2 diabetes were 65 years and older. The only difference in safety or effectiveness in this subpopulation compared to the entire study population was an expected higher incidence of cardiovascular events in both insulin glargine and NPH human insulin treated 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 (See WARNINGS AND PRECAUTIONS, Hypoglycemia). In the elderly, progressive deterioration of renal function may lead to steady decrease in insulin requirements. Careful glucose monitoring and dose adjustments of insulin or insulin analogues including LANTUS(r) may be necessary (See WARNINGS AND PRECAUTIONS, Renal).

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Type 1 and type 2 diabetes in adults:

The adverse events most commonly associated with LANTUS(r) [insulin glargine injection (rDNA origin)] include the following:

Body as a whole: allergic reaction (see WARNINGS AND PRECAUTIONS)

Hypoglycemia: Hypoglycemia, a frequent adverse reaction to insulin therapy, may occur if the insulin dose is too high in relation to the insulin requirement.

As with all insulins, prolonged or severe hypoglycemic attacks, especially if recurrent, may lead to neurological damage, loss of consciousness, coma or death (see WARNINGS and PRECAUTIONS).

Skin and appendages: injection site reaction, lipodystrophy, pruritus, and rash (see WARNINGS AND PRECAUTIONS).

Other: antibodies formation (see WARNINGS and PRECAUTIONS).

Eyes

A marked change in glycemic control may cause temporary visual impairment, due to temporary alteration in the turgidity and refractive index of the lens.

Long-term improved glycemic control decreases the risk of progression of diabetic retinopathy. However, as for all insulin regimens, intensification of insulin therapy with abrupt improvement in glycemic control may be associated with temporary worsening of diabetic retinopathy.

In patients with proliferative retinopathy, particularly if not treated with photocoagulation, severe hypoglycemic episodes may result in transient amaurosis.

Retinopathy was evaluated in the clinical studies by means of retinal adverse events reported and fundus photography. The numbers of retinal adverse events reported for LANTUS(r) and human NPH treatment groups were similar for patients with type 1 and type 2 diabetes. Progression of retinopathy was investigated by fundus photography using a grading protocol derived from the Early Treatment Diabetic Retinopathy Study (ETDRS). In one clinical study involving patients

with type 2 diabetes, a difference in the number of subjects with $3-step progression in ETDRS scale over a 6-month period was noted by fundus photography (7.5% in LANTUS(r) group versus 2.7% in human NPH treated group). The overall relevance of this isolated finding cannot be determined due to the small number of patients involved, the short follow-up period, and the fact that this finding was not observed in other clinical studies.

Type 1 diabetes in children and adolescents:

Adverse events that occurred in a pediatric controlled trial in at least 1% of patients treated with LANTUS(r) are shown below.

Table 1. Adverse Events by Body System >=1% reported in Study 3003. (Percent Incidence)

Adverse event (diagnosis) Number (%) of subjects

Body System/Coded Term LANTUS(r) n= 174

Human NPH n=175

Body as a whole

Infection 24 (13.8) 31 (17.7)

Accidental injury 5 (2.9) 4 (2.3)

Abdominal pain 2 (1.1) 2 (1.1)

Allergic reaction 2 (1.1) - ( - )

Flu syndrome - ( - ) 3 (1.7)

Pain in extremity 2 (1.1) - ( - )

Digestive system

Gastroenteritis 8 (4.6) 10 (5.7)

Diarrhea 2 (1.1) 2 (1.1)

Sore throat 2 (1.1) - ( - )

Endocrine system

Diabetes mellitus 1 (0.6) 4 (2.3)

Injection site reactions

Injection site mass	8 (4.6)	6 (3.4)
Injection site reaction	5 (2.9)	6 (3.4)
Injection site hemorrhage	2 (1.1)	2 (1.1)
Metabolic and nutritional disorders
Hypoglycemic reaction *	3 (1.7)	7 (4.0)
Hyperglycemia	1 (0.6)	3 (1.7)
Ketosis	1 (0.6)	5 (2.9)
Lipodystrophy	3 (1.7)	2 (1.1)
Musculo-skeletal system Bone fracture (not spontaneous)	3 (1.7)	3 (1.7)
Bone disorder	2 (1.1)	- ( - )
Nervous system Headache	6 (3.4)	5 (2.9)
Respiratory system Upper respiratory infection	24 (13.8)	28 (16.0)
Pharyngitis	13 (7.5)	15 (8.6)
Rhinitis	9 (5.2)	9 (5.1)
Bronchitis	6 (3.4)	7 (4.0)
Sinusitis	5 (2.9)	5 (2.9)
Asthma	1 (0.6)	2 (1.1)
Cough increased	3 (1.7)	- ( - )
Skin and appendages Fungal dermatitis	1 (0.6)	2 (1.1)
Skin benign neoplasm	1(0.6)	2 (1.1)
Eczema	2 (1.1)	1 (0.6)
Herpes zoster	2 (1.1)	1 (0.6)
Urticaria	2 (1.1)	- ( - )

*Non-serious hypoglycemia episodes are reported separately.

Study 3003: The most commonly reported event was lipodystrophy, a known consequence of insulin injections. The intensity was mostly mild. Injection site events were assessed as possibly related in 9 (5.2%) LANTUS(r) subjects and 5 (2.9%) human NPH subjects however none of these subjects discontinued due to these events.

Study 3013: extension of Study 3003, uncontrolled long-term follow-up study of 143 patients who were well-controlled on LANTUS (r) from 3003, for 201-1159 days. The most common adverse events were upper respiratory infections, infection, and rhinitis. Note that when comparing safety findings between studies, the difference in length of exposure needs to be kept in mind.

Study 4005: controlled, randomized, double-cross-over: 26 subjects (age range 12 - 20), regimen of LANTUS(r) + lispro vs. human NPH + human regular. Adverse events were equally distributed between the two treatment regimens. The most common adverse events were upper respiratory tract infection and gastroenteritis.

Patients in the pediatric clinical trials of LANTUS(r) were treated with a human NPH-based regimen pre-study, and patients assigned to receive human NPH during the study began study treatment on the same human NPH regimen they had taken pre-study. This may have been a factor in the increased incidence of hypoglycemia seen in LANTUS(r) -treated patients during (but not following) initial titration in these trials, as an increase in hypoglycemia may be expected when switching from one insulin to another and titrating the dose of the new insulin.

DRUG INTERACTIONS

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

Substances that may increase the blood-glucose-lowering effect and susceptibility to hypoglycemia, for example: oral antidiabetic products, ACE inhibitors, disopyramide, fibrates, fluoxetine, MAO inhibitors, pentoxifylline, propoxyphene, salicylates, somatostatin analog (e.g. octreotide), sulfonamide antibiotics.

Substances that may reduce the blood-glucose-lowering effect, for example: corticosteroids, danazol, diazoxide, diuretics, sympathomimetic agents (e.g., epinephrine, salbutamol, 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. 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.

DOSAGE AND ADMINISTRATION

LANTUS(r) [insulin glargine injection (rDNA origin)] is a novel recombinant human insulin analogue. Its potency is approximately the same as human insulin. It exhibits a glucose-lowering profile with no pronounced peak with a prolonged duration of action that permits once-daily basal dosing. LANTUS(r) is administered subcutaneously once a day. It may be administered at any time during the day as long as it is administered at the same time everyday.

The desired blood glucose levels as well as the doses and timing of antidiabetic medications must be determined and adjusted individually.

Dose adjustment may be required, for example, if the patient's timing of administration, weight or lifestyle changes or other circumstances arise that increase susceptibility to hypoglycemia or hyperglycemia (See WARNINGS AND PRECAUTIONS: Hypoglycemia). The dose may also have to be adjusted during intercurrent illness. (See WARNINGS AND PRECAUTIONS: Intercurrent Conditions). Any change in insulin dose should be made under medical supervision.

The prolonged duration of activity of LANTUS(r) is dependent on injection into subcutaneous space. LANTUS(r) is not intended for intravenous or intramuscular administration. Intravenous administration of the usual subcutaneous dose could result in severe hypoglycemia (See WARNINGS AND PRECAUTIONS).

In cases of insufficient glucose control or a tendency to hyper- or hypoglycemic episodes, patient's compliance with the prescribed insulin regimen, injections sites and proper injection techniques, the handling of injection devices and all other relevant factors must be reviewed before dose adjustment is considered.

LANTUS(r) must not be used for the treatment of diabetic ketoacidosis. Intravenous short-acting insulin should be the preferred treatment.

In clinical studies with insulin naive patients with type 2 diabetes, LANTUS(r) was started at a dose of 10 U once daily, and subsequently adjusted according to the patient's need (See CLINICAL TRIALS).

When changing from a treatment regimen with an intermediate or long-acting insulin to a regimen with LANTUS(r), the amount and timing of short-acting insulin or fast-acting insulin analogue or the dose of any oral antidiabetic drug may need to be adjusted secondary to the risk of hypoglycemia. In clinical studies when patients were transferred from once-daily NPH human insulin or ultralente human insulin to once-daily LANTUS(r), the initial dose was usually not changed.

However, in studies when patients were transferred from twice-daily NPH human insulin to LANTUS(r) once daily, the initial dose (U) was usually reduced by approximately 20% (compared to total daily IU of NPH human insulin) and then adjusted based on patient response.

A program of close metabolic monitoring under medical supervision is recommended during transfer and in the initial weeks thereafter. The amount and timing of short-acting insulin or fast- acting insulin analogue may need to be adjusted. This is particularly true for patients with acquired antibodies to human insulin needing high-insulin doses and occurs with all insulin analogues. Such patients may experience a greater insulin response to LANTUS(r).

With improved metabolic control and resulting increase in insulin sensitivity, further adjustment of the dose of LANTUS(r) and other insulins or oral antidiabetic drugs in the regimen may become necessary.

LANTUS(r) is administered by subcutaneous injection. The injection area must not be rubbed. As with all insulins, injection sites within an injection area (abdomen, thigh or deltoid) must be

alternated from one injection to the next. Patients should be rigorous with site rotation secondary

to prolonged deposition. In clinical studies, there was no 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.

Preparation and handling:

Parenteral drug products should be inspected visually prior to administration whenever the solution and the container permit. LANTUS(r) must only be used if the solution is clear and colorless with no particles visible. To minimize local irritation at the injection site, it is recommended to allow the insulin to reach room temperature before injection.

Cartridge /cartridge system versions only: If the injection pen malfunctions, LANTUS(r) may be drawn from the cartridge/ cartridge system into a U 100 syringe and injected. A new sterile syringe must be used.

Mixing and diluting:

LANTUS(r) must not be mixed with any other insulin. Mixing can change the time/action profile of LANTUS(r) and cause precipitation.

LANTUS(r) must not be diluted. Diluting can change the time/action profile of LANTUS(r).

OVERDOSAGE

Symptoms: An excess of insulin relative to food intake, energy expenditure or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia (See WARNINGS AND PRECAUTIONS).

Management: Mild episodes of hypoglycemia can usually be treated with oral carbohydrates. 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.

After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid reoccurrence of hypoglycemia.

ACTION AND CLINICAL PHARMACOLOGY

The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogues lower blood glucose levels by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis.

Insulin glargine is a human insulin analogue designed to have low solubility at neutral pH. At pH 4, as in the LANTUS(r) injection solution, it 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 allows once- daily dosing to meet a patient's basal insulin needs.

Insulin glargine and human insulin have been shown to be equipotent in glucose-lowering effect on a molar basis (when administered intravenously at the same doses). 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 human 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 human insulin.

shows results from a study in patients with type 1 diabetes conducted for a maximum of 24 hours after the injection. The median time between injection and the end of pharmacological effect was 14.5 hours (range: 9.5 to 19.3 hours) for NPH human insulin, and 24 hours (range:

to >24.0 hours) (24 hours was the end of the observation period) for insulin glargine.

*Determined as amount of glucose infused to maintain constant plasma glucose levels (hourly mean values). Indicative of insulin activity. Between-patient variability (CV, coefficient of variation), insulin glargine, 84% and human NPH, 78%

Absorption and Bioavailability. After subcutaneous injection of insulin glargine in healthy subjects, and 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 human insulin. Serum insulin concentrations were thus consistent with the time profile of the pharmacodynamic activity of insulin glargine.

After subcutaneous injection of 0.3 U/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 man 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 similar in vitro activity to insulin, M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr- insulin). Unchanged drug and degradation products are also present in the circulation.

Age, race, and gender: Information on the effect of age, race, and gender on the pharmacokinetics of LANTUS(r) is unavailable. However, in controlled clinical trials in adults (n=3890, Studies 3001, 3002, 3004, 3005, and 3006), and a controlled clinical trial in pediatric patients (n=349, Study 3003) subgroup analyses based on age, race (white, black, Asian /oriental, multiracial and Hispanic) and gender did not show differences in safety and efficacy between insulin glargine and NPH human insulin.

Hepatic Insufficiency: No studies were performed in patients with hepatic insufficiency. 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 or insulin analogues including LANTUS(r) may be necessary in patients with hepatic dysfunction (See WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreas).

Renal Insufficiency: No studies were performed in patients with renal insufficiency. 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 or insulin analogues including LANTUS(r) may be necessary in patients with renal dysfunction (See WARNINGS AND PRECAUTIONS, Renal).

Pregnancy: The effect of pregnancy on the pharmacokinetics and pharmacodynamics of LANTUS(r) has not been studied (See WARNINGS AND PRECAUTIONS, Special Populations).

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 any differences in safety and efficacy between insulin glargine and NPH human insulin.

Smoking: Information on the effect of smoking on the pharmacokinetics of LANTUS(r) is unavailable.

The longer duration of action (up to 24 hours) of LANTUS(r) is directly related to its slower rate of absorption and supports once-daily subcutaneous administration. The time course of action of insulins including LANTUS(r) may vary between individuals and/or within the same individual. The doses and timing of antidiabetic medications must be determined and adjusted individually, to achieve the desired blood glucose levels.

STORAGE AND STABILITY

Unopened Vial:

Unopened LANTUS(r) vials should be stored in a refrigerator, between 2degC - 8degC. LANTUS(r) should not be stored in the freezer and it should not be allowed to freeze. If refrigeration is not possible, unopened LANTUS(r) can be kept unrefrigerated (15 - 30degC) for up to 28 days away from direct heat and light, as long as the temperature is not greater than 30degC. If LANTUS(r) freezes or overheats, discard it.

Opened (In Use) Vial:

Opened LANTUS(r) vials, whether or not refrigerated, must be discarded after 28 days even if they contain insulin. The opened vial can also be kept unrefrigerated (15 - 30degC) for up to 28 days away from direct heat and light, as long as the temperature is not greater than 30degC.

Opened LANTUS(r) vials should not be stored in the freezer and should not be allowed to freeze. If a vial freezes or overheats, discard it.

Unopened Cartridge:

Unopened LANTUS(r) cartridges should be stored in a refrigerator, between 2degC - 8degC. LANTUS(r) should not be stored in the freezer and it should not be allowed to freeze. If

refrigeration is not possible, unopened LANTUS(r) can be kept unrefrigerated (15 - 30EC) for up

to 28 days away from direct heat and light, as long as the temperature is not greater than 30EC. If LANTUS(r) freezes or overheats, discard it.

Opened (In Use) Cartridge:

The opened cartridge in use must be kept unrefrigerated (15 - 30degC) for up to 28 days away from direct heat and light, as long as the temperature is not greater than 30degC. If the cartridge overheats or if there is any remaining insulin after 28 days, discard it. The opened cartridge in use must never be removed from and reinserted into the injection pen.

Unopened Cartridge System:

Unopened LANTUS(r) cartridge systems should be stored in a refrigerator, between 2degC - 8degC. LANTUS(r) should not be stored in the freezer and it should not be allowed to freeze. If

refrigeration is not possible, unopened LANTUS(r) can be kept unrefrigerated (15 - 30EC) for up

to 28 days away from direct heat and light, as long as the temperature is not greater than 30EC. If LANTUS(r) freezes or overheats, discard it.

Opened (In Use) Cartridge System:

The opened cartridge system in use must be kept unrefrigerated (15 - 30degC) for up to 28 days away from direct heat and light, as long as the temperature is not greater than 30degC. If the cartridge system overheats or if there is any remaining insulin after 28 days, discard it. The opened cartridge system in use must never be removed from and reinserted into the OptiClik(tm).

Unopened OptiSet(tm):

Unopened LANTUS(r) OptiSet(tm) should be stored in a refrigerator, between 2degC - 8degC. LANTUS(r) OptiSet(tm) should not be stored in the freezer and it should not be allowed to freeze. If refrigeration is not possible, unopened LANTUS(r) OptiSet(tm) can be kept unrefrigerated (15degC

30degC) for up to 28 days away from direct heat and light, as long as the temperature is not greater than 30degC. If LANTUS(r) OptiSet(tm) freezes or overheats, discard it.

Opened OptiSet(tm):

Opened LANTUS(r) OptiSet(tm) in use must be kept unrefrigerated (15-30degC) for up to 28 days away from direct heat and light, as long as the temperature is not greater than 30degC. If the LANTUS(r) OptiSet(tm) overheats or if there is any remaining insulin after 28 days, discard it.

Opened LANTUS(r) OptiSetTM should not be stored in the freezer and should not be allowed to freeze. If LANTUS(r) OptiSet(tm) freezes discard it.

Unopened SoloStar(tm):

Unopened LANTUS(r) SoloStar(tm) should be stored in a refrigerator, between 2degC - 8degC. LANTUS(r) SoloStar(tm) should not be stored in the freezer and it should not be allowed to freeze. If refrigeration is not possible, unopened LANTUS(r) SoloStar(tm) can be kept unrefrigerated (15degC - 30degC) for up to 28 days away from direct heat and light, as long as the temperature is not greater than 30degC. If LANTUS(r) SoloStar(tm) freezes or overheats, discard it.

Opened SoloStar(tm):

Opened LANTUS(r) SoloStar(tm) in use must be kept unrefrigerated (15-30degC) for up to 28 days away from direct heat and light, as long as the temperature is not greater than 30degC. If the LANTUS(r) SoloStar(tm) overheats or if there is any remaining insulin after 28 days, discard it.

Opened LANTUS(r) SoloStar(tm) should not be stored in the freezer and should not be allowed to freeze. If LANTUS(r) SoloStar(tm) freezes discard it.

SPECIAL HANDLING INSTRUCTIONS

LANTUS(r) must only be used if the solution is clear and colorless with no particles visible (See DOSAGE and ADMINISTRATION: Administration). LANTUS(r) is a clear solution, not a suspension. LANTUS (r) can be confused with other insulin types, since it visually resembles short-acting insulins and its name resembles the 'Lente' brand of insulins. It is not necessary to shake or rotate the vial/cartridge/cartridge system/ OptiSet(tm)/SoloStar(tm) before use. Patients must be advised that LANTUS(r) must not be mixed with any other insulin or diluted with any other solution (See WARNINGS AND PRECAUTIONS, General).

Patients should be instructed on self-management procedures including glucose monitoring, proper injection technique, and hypoglycemia and hyperglycemia management. Patients must be instructed 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. The extent of patient participation in his/her diabetes management is variable and is generally determined by the physician.

Insulin treatment requires constant alertness to the possibility of hyper- and hypoglycemia. Patients and their relatives must know what steps to take if hyperglycemia or hypoglycemia occurs or is suspected, and they must know when to inform a physician.

Patients with diabetes should be advised to inform their doctor if they are pregnant or are contemplating pregnancy.

As with all patients who have diabetes, the ability to concentrate and/or react may be impaired as a result of hypoglycemia or hyperglycemia. Patients should be advised to take precautions to avoid hypoglycemia while driving. This is particularly important in those who have reduced or absent awareness of the warning symptoms of hypoglycemia or have frequent episodes of hypoglycemia. The advisability of driving should be considered in these circumstances.

See also INFORMATION FOR THE PATIENT and refer patients to the LANTUS(r) Information for the Patient circular for LANTUS(r) VIALS, LANTUS(r) CARTRIDGE, LANTUS(r)

CARTRIDGE SYSTEM, LANTUS(r) OPTISET(tm) and LANTUS(r) SOLOSTAR(tm) for additional information. Refer patients to the User Manual for Optipen(r) Pro or injection pens suitable for LANTUS(r) cartridges AS RECOMMENDED IN THE INFORMATION PROVIDED BY THE

INJECTION PEN MANUFACTURER, User Manual for OptiClik(tm), User Manual for the LANTUS(r) OptiSet(tm), and User Manual for the LANTUS(r) SoloStar(tm), for additional information on use of the pens.

DOSAGE FORMS, COMPOSITION AND PACKAGING

The vials, cartridges, cartridge systems, OptiSet(tm), and SoloStar(tm) contain a sterile solution of insulin glargine for use as an injection. LANTUS(r) [insulin glargine injection (rDNA origin)] consists of insulin glargine dissolved in a clear aqueous fluid.

Each milliliter of LANTUS(r) (insulin glargine injection) contains insulin glargine 100 units. Each milliliter also contains excipients: glycerol 85%, polysorbate 20 (10 mL vial only), m-cresol, zinc, and water for injection. LANTUS(r) has a pH of approximately 4. The pH is adjusted by addition of aqueous solutions of hydrochloric acid and sodium hydroxide.

LANTUS(r) [insulin glargine (rDNA origin)] 100 units per mL (U 100) is available in the following package sizes:

Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients
Subcutaneous	Solution for injection 100 U/mL	glycerol 85%, m-cresol, polysorbate 20 (10 mL vial only), zinc, and water for injection. Hydrochloric acid and sodium hydroxide for pH adjustment.

LANTUS(r)

PART I: HEALTH PROFESSIONAL INFORMATION 3

PART II: SCIENTIFIC INFORMATION 21

PART III: CONSUMER INFORMATION. 34

PART III: CONSUMER INFORMATION. 40

PART III: CONSUMER INFORMATION. 47

PART III: CONSUMER INFORMATION. 53

PART III: CONSUMER INFORMATION. 59

PRODUCT MONOGRAPH

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

DESCRIPTION

INDICATIONS AND CLINICAL USE