LANTUS  - insulin glargine injection, solution 
Physicians Total Care, Inc.

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FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE

LANTUS is 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:

2. DOSAGE AND ADMINISTRATION

2.1 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 [see Warnings and Precautions (5.1).]

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 [see Clinical pharmacology (12.2)]. LANTUS should not be administered intravenously or via an insulin pump. Intravenous administration of the usual subcutaneous dose could result in severe hypoglycemia [see Warnings and Precautions (5.3)].

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 [See Adverse Reactions (6.1)].

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.

2.2 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.

2.3 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.

3. DOSAGE FORMS AND STRENGTHS

LANTUS solution for injection 100 Units per mL is available as:

- 10 mL Vial (1000 Units/10 mL) - 3 mL Cartridge systems for use only in OptiClik® (300 Units/3 mL) - 3 mL SoloStar® disposable insulin device (300 Units/3 mL)

4. CONTRAINDICATIONS

LANTUS is contraindicated in patients with hypersensitivity to LANTUS or one of its excipients.

5. WARNINGS AND PRECAUTIONS

5.1 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.

5.2 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 [see Warnings and Precautions (5.3)].

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.

5.3 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 [See Drug Interactions (7)].

The prolonged effect of subcutaneous LANTUS may delay recovery from hypoglycemia. Patients being switched from twice daily NPH insulin to once-daily LANTUS should have their initial LANTUS dose reduced by 20% from the previous total daily NPH dose to reduce the risk of hypoglycemia [see Dosage and Administration (2.3)].

As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food intake). The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.

Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic neuropathy, use of medications such as beta-blockers, or intensified glycemic control. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient's awareness of hypoglycemia.

5.4 Hypersensitivity and allergic reactions

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

5.5 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)].

5.6 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. [See Clinical Pharmacology (12.3)].

5.7 Drug interactions

Some medications may alter insulin requirements and subsequently increase the risk for hypoglycemia or hyperglycemia [See Drug Interactions (7)].

6. ADVERSE REACTIONS

The following adverse reactions are discussed elsewhere:

6.1 Clinical trial experience

Because clinical trials are conducted under widely varying designs, 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 frequencies of treatment-emergent adverse events during LANTUS clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.

Table 1: Treatment –emergent adverse events in pooled clinical trials up to 28 weeks duration in adults with type 1 diabetes (adverse events with frequency greater than or equal to 5%)

LANTUS, %
(n=1257)		NPH, %
(n=1070)
Upper respiratory tract infection
22.4
23.1
Infection   (*)
9.4
10.3
Accidental injury
5.7
6.4
Heachache
5.5
4.7

(*)   Body System not Specified

Table 2: Treatment –emergent adverse events in pooled clinical trials up to 1 year duration in adults with type 2 diabetes (adverse events with frequency greater than or equal to 5%)

LANTUS, %
(n=849)		NPH, %
(n=714)
Upper respiratory tract infection
11.4
13.3
Infection   (*)
10.4
11.6
Retinal vascular disorder
5.8
7.4

(*)   Body System not Specified

Table 3: Treatment –emergent adverse events in a 5-year trial of adults with type 2 diabetes (adverse events with frequency greater than or equal to 10%)

LANTUS, %
(n=514)		NPH, %
(n=503)
Upper respiratory tract infection
29.0
33.6
Edema peripheral
20.0
22.7
Hypertension
19.6
18.9
Influenza
18.7
19.5
Sinusitis
18.5
17.9
Cataract
18.1
15.9
Bronchitis
15.2
14.1
Arthralgia
14.2
16.1
Pain in extremity
13.0
13.1
Back pain
12.8
12.3
Cough
12.1
7.4
Urinary tract infection
10.7
10.1
Diarrhea
10.7
10.3
Depression
10.5
9.7
Heachache
10.3
9.3

Table 4: Treatment –emergent adverse events in a 28-week clinical trial of children and adolescents with type 1 diabetes (adverse events with frequency greater than or equal to 5%)

LANTUS, %
(n=174)		NPH, %
(n=175)
Infection   (*)
13.8
17.7
Upper respiratory tract infection
13.8
16.0
Pharyngitis
7.5
8.6
Rhinitis
5.2
5.1
(*)   Body System no Specified

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including LANTUS [See Warnings and Precautions (5.3)]. Tables 5 and 6 summarize the incidence of severe hypoglycemia in the LANTUS individual clinical trials. Severe symptomatic hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a blood glucose below 50 mg/dL (≤56 mg/dL in the 5-year trial) or prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration.

The rates of severe symptomatic hypoglycemia in the LANTUS clinical trials (see Section 14 for a description of the study designs) were comparable for all treatment regimens (see Tables 5 and 6). In the pediatric phase 3 clinical trial, children and adolescents with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to the adult trials with type 1 diabetes. (see Table 5) [See Clinical Studies (14)].

Table 5: Severe Symptomatic Hypoglycemia in Patients with Type 1 Diabetes

Study A
Diabetes Adults
In combination
regular 		Type 1
28 weeks
with
insulin		Study B
Diabetes Adults
 In combination
regular		Type 1
28 weeks
 with
insulin 		Study C
Diabetes Adults
In combination
insulin		Type 1
16 weeks
with
lispro
Study D
Diabetes Pediatrics
In combination
regular 		Type 1
26 weeks
 with
insulin

LANTUSNPHLANTUSNPHLANTUSNPHLANTUSNPH
Percent of
patients (n/total
N)
10.6
(31/292)
15.0
(44/293)
8.7
(23/264)
10.4
(28/270)
6.5
(20/310)
5.2
(16/309)
23.0
(40/174)
28.6
(50/175)


Table 6: Severe Symptomatic Hypoglycemia in Patients with Type 2 Diabetes

Study E
Diabetes Adults
In combination
oral
Type 2
52 weeks
with
agents
Study F
Diabetes Adults
In combination
regular
 Type 2
28 weeks
with
insulin
Study G
Diabetes Adults
In combination
regular
Type 2
5 years
with
insulin

LANTUSNPH
LANTUS
NPH
LANTUS
NPH
Percent of
patients (n/total
N)
1.7
(5/289)
1.1
(3/281)
0.4
(1/259)
2.3
(6/259)
7.8
(40/513)
11.9
(60.504)

Retinopathy was evaluated in the LANTUS clinical studies by analysis of reported retinal adverse events and fundus photography. The numbers of retinal adverse events reported for LANTUS and NPH insulin treatment groups were similar for patients with type 1 and type 2 diabetes.

LANTUS was compared to NPH insulin in a 5-year randomized clinical trial that evaluated the progression of retinopathy as assessed with fundus photography using a grading protocol derived from the Early Treatment Diabetic Retinopathy Scale (ETDRS). Patients had type 2 diabetes (mean age 55 yrs) with no (86%) or mild (14%) retinopathy at baseline. Mean baseline HbA1c was 8.4%. The primary outcome was progression by 3 or more steps on the ETDRS scale at study endpoint. Patients with pre-specified post-baseline eye procedures (pan-retinal photocoagulation for proliferative or severe nonproliferative diabetic retinopathy, local photocoagulation for new vessels, and vitrectomy for diabetic retinopathy) were also considered as 3-step progressors regardless of actual change in ETDRS score from baseline. Retinopathy graders were blinded to treatment group assignment. The results for the primary endpoint are shown in Table 7 for both the per-protocol and Intent-to-Treat populations, and indicate similarity of Lantus to NPH in the progression of diabetic retinopathy as assessed by this outcome.

Table 7. Number (%) of patients with 3 or more step progression on ETDRS scale at endpoint

Lantus (%)NPH (%)Difference  (*,**) 
(SE)		95% CI for difference
Per-protocol                   
53/374 (14.2%)
57/363 (15.7%)
-2.0% (2.6%)
-7.0% to +3.1%
Intent-to-Treat
63/502 (12.5%)
71/487 (14.6%)
-2.1% (2.1%)
-6.3% to +2.1%

(*)   Difference = Lantus - NPH
(**) using a generalized linear model (SAS GENMOD) with treatment and baseline HbA1c strata (cutoff 9.0%) as the classified independent variables, and with binomial distribution and identity link function

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.

Long-term use of insulin, including LANTUS, 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. Rotate insulin injection or infusion sites within the same region to reduce the risk of lipodystrophy. [See Dosage and Administration (2.1)].

Weight gain can occur with insulin therapy, including LANTUS, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.

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

Local Allergy

As with any insulin therapy, patients taking LANTUS may experience injection site reactions, including redness, pain, itching, urticaria, edema, and inflammation. In clinical studies in adult patients, there was a higher incidence of treatment-emergent injection site pain in LANTUS-treated patients (2.7%) compared to NPH insulin-treated patients (0.7%). The reports of pain at the injection site did not result in discontinuation of therapy.

Rotation of the injection site within a given area from one injection to the next may help to reduce or prevent these reactions. 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. Most minor reactions to insulin usually resolve in a few days to a few weeks.

Systemic Allergy

Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LANTUS and may be life threatening.

All insulin products can elicit the formation of insulin antibodies. The presence of such insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase 3 clinical trials of LANTUS, increases in titers of antibodies to insulin were observed in NPH insulin and insulin glargine treatment groups with similar incidences.

6.2 Postmarketing experience

The following adverse reactions have been identified during post-approval use of LANTUS.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure.

Medication errors have been reported in which other insulins, particularly short-acting insulins, have been accidentally administered instead of LANTUS [See Patient Counseling Information (17)]. To avoid medication errors between LANTUS and other insulins, patients should be instructed to always verify the insulin label before each injection.



7 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.

8 USE IN SPECIFIC POPULATIONS

8.1 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.

8.3 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.

8.4 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.

8.5 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 [See Warnings and Precautions (5.3)].

10 OVERDOSAGE

An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia. 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 of hypoglycemia 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 recurrence of hypoglycemia.

11 DESCRIPTION

LANTUS (insulin glargine [rDNA origin] injection) is a sterile solution of insulin glargine for use as a subcutaneous injection. Insulin glargine is a recombinant human insulin analog that is a long-acting (up to 24-hour duration of action), parenteral blood-glucose-lowering agent [See Clinical Pharmacology (12)]. LANTUS is produced by recombinant DNA technology utilizing a non-pathogenic 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 are added to the C-terminus of the B-chain. Chemically, insulin glargine is 21A-Gly-30Ba-L-Arg-30Bb-L-Arg-human insulin and has the empirical formula C267H404N72O78S6 and a molecular weight of 6063. Insulin glargine has the following structural formula:

image of Lantus chemical structure

LANTUS consists of insulin glargine dissolved in a clear aqueous fluid. Each milliliter of LANTUS (insulin glargine injection) contains 100 Units (3.6378 mg) insulin glargine.

The 10 mL vial presentation contains the following inactive ingredients per mL: 30 mcg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, 20 mcg polysorbate 20, and water for injection.

The 3 mL cartridge presentation contains the following inactive ingredients per mL: 30 mcg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, and water for injection.

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

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 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. Figure 1 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 insulin, and 24 hours (range: 10.8 to >24.0 hours) (24 hours was the end of the observation period) for insulin glargine.

Figure 1. Activity Profile in Patients with Type 1 Diabetes

image of Figure 1. Activity Profile graph

* Determined as amount of glucose infused to maintain constant plasma glucose levels (hourly mean values); indicative of insulin activity.

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.

12.3 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 [see Clinical Studies (14)].

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 [see Use in Specific Populations (8.1)].

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 [see Clinical Studies (14)].

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 [See Warnings and Precautions (5.5)].

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 [See Warnings and Precautions (5.6)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 10 times and for the mouse approximately 5 times the recommended human subcutaneous starting dose of 10 Units/day (0.008 mg/kg/day), based on mg/m2. 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 7 times the recommended human subcutaneous starting dose of 10 Units/day (0.008 mg/kg/day), based on mg/m2, 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.

14 CLINICAL STUDIES

The safety and effectiveness of LANTUS given once-daily at bedtime was compared to that of once-daily and twice-daily NPH insulin in open-label, randomized, active-controlled, parallel studies of 2,327 adult patients and 349 pediatric patients with type 1 diabetes mellitus and 1,563 adult patients with type 2 diabetes mellitus (see Tables 8–11). In general, the reduction in glycated hemoglobin (HbA1c) with LANTUS was similar to that with NPH insulin. The overall rates of hypoglycemia did not differ between patients with diabetes treated with LANTUS compared to NPH insulin [See Adverse Reactions (6.1)].

Type 1 Diabetes–Adult (see Table 8).

In two clinical studies (Studies A and B), patients with type 1 diabetes (Study A; n=585, Study B; n=534) were randomized to 28 weeks of basal-bolus treatment with LANTUS or NPH insulin. Regular human insulin was administered before each meal. LANTUS was administered at bedtime. NPH insulin was administered once daily at bedtime or in the morning and at bedtime when used twice daily.

In another clinical study (Study C), patients with type 1 diabetes (n=619) were randomized to 16 weeks of basal-bolus treatment with LANTUS or NPH insulin. Insulin lispro was used before each meal. LANTUS was administered once daily at bedtime and NPH insulin was administered once or twice daily.

In these 3 studies, LANTUS and NPH insulin had similar effects on HbA1c (Table 8) with a similar overall rate of hypoglycemia [See Adverse Reactions (6.1)].

Table 8: Type 1 Diabetes Mellitus–Adult


Study A

Study B

Study C
Treatment duration
28 weeks

28 weeks

16 weeks
Treatment in combination with
Regular insulin

Regular insulin

Insulin lispro

LANTUS
NPHLANTUS
NPHLANTUS
NPH
Number of subjects treated
292
293
264
270
310
309
HbA1c








   Baseline HbA1c
8.0
8.0
7.7
7.7
7.6
7.7
      Adj. mean change from baseline
+0.2
+0.1
-0.2
-0.2
-0.1
-0.1
      LANTUS - NPH
+0.1

+0.1

0.0
      95% CI for Treatment difference
(0.0; +0.2)

(-0.1; +0.2)

(-0.1; +0.1)
Basal insulin dose








   Baseline mean
21
23
29
29
28
28
   Mean change from baseline
-2
0
-4
+2
-5
+1
Total insulin dose








   Baseline mean
48
52
50
51
50
50
   Mean change from baseline
-1
0
0
+4
-3
0
Fasting blood glucose (mg/dL)








   Baseline mean
167
166
166
175
175
173
   Adj. mean change from baseline
-21
-16
-20
-17
-29
-12
Body weight (kg)








   Baseline mean
73.2
74.8
75.5
75.0
74.8
75.6
  Mean change from baseline
0.1
-0.0
0.7
1.0
0.1
0.5

Type 1 Diabetes–Pediatric (see Table 9).

In a randomized, controlled clinical study (Study D), pediatric patients (age range 6 to 15 years) with type 1 diabetes (n=349) were treated for 28 weeks with a basal-bolus insulin regimen where regular human insulin was used before each meal. LANTUS was administered once daily at bedtime and NPH insulin was administered once or twice daily. Similar effects on HbA1c (Table 9) and the incidence of hypoglycemia were observed in both treatment groups [See Adverse Reactions (6.1)].

Table 9: Type 1 Diabetes Mellitus–Pediatric


Study D
Treatment duration
28 weeks
Treatment in combination with
Regular insulin

LANTUS
NPH
Number of subjects treated
174
175
HbA1c


   Baseline mean
8.5
8.8
   Adj. mean change from baseline
+0.3
+0.3
      LANTUS - NPH
0.0
      95% CI for Treatment difference
(-0.2; +0.3)
Basal insulin dose


   Baseline mean
19
19
   Mean change from baseline
-1
+2
Total insulin dose


   Baseline mean
43
43
   Mean change from baseline
+2
+3
Fasting blood glucose (mg/dL)


   Baseline mean
194
191
   Adj. mean change from baseline
-23
-12
Body weight (kg)


   Baseline mean
45.5
44.6
   Mean change from baseline
2.2
2.5

Type 2 Diabetes–Adult (see Table 10).

In a randomized, controlled clinical study (Study E) (n=570), LANTUS was evaluated for 52 weeks in combination with oral anti-diabetic medications (a sulfonylurea, metformin, acarbose, or combinations of these drugs). LANTUS administered once daily at bedtime was as effective as NPH insulin administered once daily at bedtime in reducing HbA1c and fasting glucose (Table 10). The rate of hypoglycemia was similar in LANTUS and NPH insulin treated patients [See Adverse Reactions (6.1)].

In a randomized, controlled clinical study (Study F), in patients with type 2 diabetes not using oral anti-diabetic medications (n=518), a basal-bolus regimen of LANTUS once daily at bedtime or NPH insulin administered once or twice daily was evaluated for 28 weeks. Regular human insulin was used before meals, as needed. LANTUS had similar effectiveness as either once- or twice-daily NPH insulin in reducing HbA1c and fasting glucose (Table 10) with a similar incidence of hypoglycemia [See Adverse Reactions (6.1)].

In a randomized, controlled clinical study (Study G), patients with type 2 diabetes were randomized to 5 years of treatment with once-daily LANTUS or twice-daily NPH insulin. For patients not previously treated with insulin, the starting dose of LANTUS or NPH insulin was 10 units daily. Patients who were already treated with NPH insulin either continued on the same total daily NPH insulin dose or started LANTUS at a dose that was 80% of the total previous NPH insulin dose. The primary endpoint for this study was a comparison of the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. HbA1c change from baseline was a secondary endpoint. Similar glycemic control in the 2 treatment groups was desired in order to not confound the interpretation of the retinal data. Patients or study personnel used an algorithm to adjust the LANTUS and NPH insulin doses to a target fasting plasma glucose ≤100 mg/dL. After the LANTUS or NPH insulin dose was adjusted, other anti-diabetic agents, including pre-meal insulin were to be adjusted or added. The LANTUS group had a smaller mean reduction from baseline in HbA1c compared to the NPH insulin group, which may be explained by the lower daily basal insulin doses in the LANTUS group (Table 10). Both treatment groups had a similar incidence of reported symptomatic hypoglycemia. The incidences of severe symptomatic hypoglycemia are given in Table 6 [See Adverse Reactions (6.1)].

Table 10: Type 2 Diabetes Mellitus–Adult


Study E

Study F

Study G
Treatment duration
52 weeks

28 weeks

5 years
Treatment in combination with
Oral agents

Regular insulin

Regular insulin

LANTUS
NPHLANTUS
NPHLANTUS
NPH
Number of subjects treated
289
281
259
259
513
504
HbA1c








   Baseline mean
9.0
8.9
8.6
8.5
8.4
8.3
   Adj. mean change from baseline
-0.5
-0.4
-0.4
-0.6
-0.6
-0.8
      LANTUS - NPH
-0.1

+0.2

+0.2
      95% CI for Treatment difference
(-0.3; +0.1)

(0.0; +0.4)

(+0.1; +0.4)
Basal insulin dose    (*)








   Baseline mean
14
15
44.1
45.5
39
44
   Mean change from baseline
+12
+9
-1
+7
+23
+30
Total insulin dose   (*)








   Baseline mean
14
15
64
67
48
53
   Mean change from baseline
+12
+9
+10
+13
+41
+40
Fasting blood glucose (mg/dL)








   Baseline mean
179
180
164
166
190
180
   Adj. mean change from baseline
-49
-46
-24
-22
-45
-44
Body weight (kg)








   Baseline mean
83.5
82.1
89.6
90.7
100
99
   Adj. mean change from baseline
2.0
1.9
0.4
1.4
3.7
4.8

(*)    In Study G, the baseline dose of basal or total insulin was the first available on-treatment dose prescribed during the study (on visit month 1.5).

LANTUS Timing of Daily Dosing (see Table 11).

The safety and efficacy of LANTUS administered pre-breakfast, pre-dinner, or at bedtime were evaluated in a randomized, controlled clinical study in patients with type 1 diabetes (study H, n=378). Patients were also treated with insulin lispro at mealtime. LANTUS administered at different times of the day resulted in similar reductions in HbA1c compared to that with bedtime administration (see Table 11). In these patients, data are available from 8-point home glucose monitoring. The maximum mean blood glucose was observed just prior to injection of LANTUS regardless of time of administration.

In this study, 5% of patients in the LANTUS-breakfast arm discontinued treatment because of lack of efficacy. No patients in the other two arms discontinued for this reason. The safety and efficacy of LANTUS administered pre-breakfast or at bedtime were also evaluated in a randomized, active-controlled clinical study (Study I, n=697) in patients with type 2 diabetes not adequately controlled on oral anti-diabetic therapy. All patients in this study also received glimepiride 3 mg daily. LANTUS given before breakfast was at least as effective in lowering HbA1c as LANTUS given at bedtime or NPH insulin given at bedtime (see Table 11).

Table 11: LANTUS Timing of Daily Dosing in Type 1 (Study H) and Type 2 (Study I) Diabetes Mellitus


Study H

Study I
Treatment duration
24 weeks

24 weeks
Treatment in combination with:
Insulin lispro

Glimepiride

LANTUSLANTUSLANTUSLANTUSLANTUSNPH

BreakfastDinnerBedtimeBreakfastBedtimeBedtime
Number of subjects treated  (*)
112
124
128
234
226
227
HbA1c





   Baseline mean
7.6
7.5
7.6
9.1
9.1
9.1
   Mean change from baseline
-0.2
-0.1
0.0
-1.3
-1.0
-0.8
Basal insulin dose (U)





   Baseline mean
22
23
21
19
20
19
   Mean change from baseline
5
2
2
11
18
18
Total insulin dose (U)


NA  (**)
NA
NA
   Baseline mean
52
52
49


   Mean change from baseline
2
3
2


Body weight (kg)





   Baseline mean
77.1
77.8
74.5
80.7
82
81
   Mean change from baseline
0.7
0.1
0.4
3.9
3.7
2.9








** total number of patients evaluable for safety
(*)   Intent to treat
(**) Not applicable




16 HOW SUPPLIED/STORAGE AND HANDLING

LANTUS solution for injection 100 units per mL (U-100) is available as:

Dose Unit/StrengthPackage SizeNDC #


54868
10 mL vialsPack of 1
4626-0
100 Units/mL

3 mL cartridge system (*)
package of 5
5765-0
100 Units/mL



(*)   Cartridge systems are for use only in OptiClik® (Insulin Delivery Device)

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.

1The brands listed are the registered trademarks of their respective owners and are not trademarks of sanofi-aventis U.S. LLC 16.2 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:



Not in-use (unopened)Not in-use (unopened)In-use
(opened)

RefrigeratedRoom Temperature



(See Temperature Below)
10 mL Vial
Until expiration date
28 days
28 days



Refrigerated or room temperature
3 mL Cartridge system
Until expiration date
28 days
28 days



Refrigerated or room temperature
3 mL Cartridge system inserted   
into OptiClik®

28 days
Room temperature only
(Do not refrigerate)

16.3 Preparation and handling

Parenteral drug products should be inspected visually prior to administration whenever the solution and the container permit. LANTUS must only be used if the solution is clear and colorless with no particles visible.

Mixing and diluting: LANTUS must NOT be diluted or mixed with any other insulin or solution [See Warnings and Precautions (5.2)].

Vial: The syringes must not contain any other medicinal product or residue.

Cartridge system/SoloStar: If OptiClik, the Insulin Delivery Device used with the LANTUS cartridge system, or SoloStar disposable insulin device, malfunctions, LANTUS may be drawn from the cartridge system or from SoloStar into a U-100 syringe and injected.


17 PATIENT COUNSELING INFORMATION

17.1 Instructions for patients

Patients should be informed that changes to insulin regimens must be made cautiously and only under medical supervision.

Patients should be informed about the potential side effects of insulin therapy, including lipodystrophy (and the need to rotate injection sites within the same body region), weight gain, allergic reactions, and hypoglycemia. Patients should be informed that the ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use caution when driving or operating machinery.

Accidental mix-ups between LANTUS and other insulins, particularly short-acting insulins, have been reported. To avoid medication errors between LANTUS and other insulins, patients should be instructed to always check the insulin label before each injection.

LANTUS must only be used if the solution is clear and colorless with no particles visible. Patients must be advised that LANTUS must NOT be diluted or mixed with any other insulin or solution.

Patients should be advised not to share disposable or reusable insulin devices or needles with other patients, because doing so carries a risk for transmission of blood-borne pathogens.

Patients should be instructed on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia. 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, and skipped meals.

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

Refer patients to the LANTUS "Patient Information" for additional information.

17.2 FDA approved patient labeling

See attached document at end of Full Prescribing Information.

Rev. September 2009

sanofi-aventis U.S. LLC

Bridgewater, NJ 08807

©2009 sanofi-aventis U.S. LLC

Patient Information
LANTUS® 10 mL vial (1000 units per vial) 100 units per mL (U-100)
(insulin glargine [recombinant DNA origin] injection)

Read this "Patient Information" that comes with LANTUS (LAN-tus) before you start using it and each time you get a refill because there may be new information. This leaflet does not take the place of talking with your healthcare provider about your condition or treatment. If you have questions about LANTUS or about diabetes, talk with your healthcare provider.

What is the most important information I should know about LANTUS?

What is Diabetes?

What is LANTUS?

Who should NOT take LANTUS?

Do not take LANTUS if you are allergic to insulin glargine or any of the inactive ingredients in LANTUS. Check with your healthcare provider if you are not sure.

Before starting LANTUS, tell your healthcare provider about all your medical conditions including if you:

How should I use LANTUS?

See the "Instructions for Use" including the "How do I draw the insulin into the syringe?" section for additional information.

What kind of syringe should I use?

Mixing with LANTUS

Instructions for Use

How do I draw the insulin into the syringe?

Follow these steps:

  1. Wash your hands with soap and water or with alcohol.
  2. Check the insulin to make sure it is clear and colorless. Do not use the insulin after the expiration date stamped on the label, if it is colored or cloudy, or if you see particles in the solution.
  3. If you are using a new vial, remove the protective cap. Do not remove the stopper.
    image of new vial, removing protective cap (#3)
  4. Wipe the top of the vial with an alcohol swab. You do not have to shake the vial of LANTUS before use.
    image of wiping top of vial (#4)
  5. Use a new needle and syringe every time you give an injection. Use disposable syringes and needles only once. Throw them away properly. Never share needles and syringes.
  6. Draw air into the syringe equal to your insulin dose. Put the needle through the rubber top of the vial and push the plunger to inject the air into the vial.
    image of drawing air into syringe (#6a)
     
    image of placing rubber top on vial (#6b)
  7. Leave the syringe in the vial and turn both upside down. Hold the syringe and vial firmly in one hand.
  8. Make sure the tip of the needle is in the insulin. With your free hand, pull the plunger to withdraw the correct dose into the syringe.
    image of tip of syringe is in vial (#8)
  9. Before you take the needle out of the vial, check the syringe for air bubbles. If bubbles are in the syringe, hold the syringe straight up and tap the side of the syringe until the bubbles float to the top. Push the bubbles out with the plunger and draw insulin back in until you have the correct dose.
    image of tapping syringe for air (#9)
  10. Remove the needle from the vial. Do not let the needle touch anything. You are now ready to inject.

How do I inject LANTUS?

Inject LANTUS under your skin. Take LANTUS as prescribed by your healthcare provider.

Follow these steps:

  1. Decide on an injection area - either upper arm, thigh or abdomen. Injection sites within an injection area must be different from one injection to the next.
  2. Use alcohol or soap and water to clean the injection site. The injection site should be dry before you inject.
    image of cleaning injection site (#2)
  3. Pinch the skin. Stick the needle in the way your healthcare provider showed you. Release the skin.
  4. Slowly push in the plunger of the syringe all the way, making sure you have injected all the insulin. Leave the needle in the skin for about 10 seconds.
    image of pushing plunger of syringe into injection site (#4)
  5. Pull the needle straight out and gently press on the spot where you injected yourself for several seconds. Do not rub the area.
  6. Follow your healthcare providers instructions for throwing away the used needle and syringe. Do not recap the used needle. Used needle and syringe 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.

What can affect how much insulin I need?

Illness. Illness may change how much insulin you need. It is a good idea to think ahead and make a "sick day" plan with your healthcare provider in advance so you will be ready when this happens. Be sure to test your blood sugar more often and call your healthcare provider if you are sick.

Medicines. Many medicines can affect your insulin needs. Other medicines, including prescription and non-prescription medicines, vitamins, and herbal supplements, can change the way insulin works. You may need a different dose of insulin when you are taking certain other medicines. Know all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. You may want to keep a list of the medicines you take. You can show this list to your healthcare provider anytime you get a new medicine or refill. Your healthcare provider will tell you if your insulin dose needs to be changed.

Meals. The amount of food you eat can affect your insulin needs. If you eat less food, skip meals, or eat more food than usual, you may need a different dose of insulin. Talk to your healthcare provider if you change your diet so that you know how to adjust your LANTUS and other insulin doses.

Alcohol. Alcohol, including beer and wine, may affect the way LANTUS works and affect your blood sugar levels. Talk to your healthcare provider about drinking alcohol.

Exercise or Activity level. Exercise or activity level may change the way your body uses insulin. Check with your healthcare provider before you start an exercise program because your dose may need to be changed.

Travel. If you travel across time zones, talk with your healthcare provider about how to time your injections. When you travel, wear your medical alert identification. Take extra insulin and supplies with you.

Pregnancy or nursing. The effects of LANTUS on an unborn child or on a nursing baby are unknown. Therefore, tell your healthcare provider if you are planning to have a baby, are pregnant, or nursing a baby. Good control of diabetes is especially important during pregnancy and nursing.

What are the possible side effects of LANTUS and other insulins?

Insulins, including LANTUS, can cause hypoglycemia (low blood sugar), hyperglycemia (high blood sugar), allergy, and skin reactions.

Hypoglycemia (low blood sugar):

Hypoglycemia is often called an "insulin reaction" or "low blood sugar". It may happen when you do not have enough sugar in your blood. Common causes of hypoglycemia are illness, emotional or physical stress, too much insulin, too little food or missed meals, and too much exercise or activity.

Early warning signs of hypoglycemia may be different, less noticeable or not noticeable at all in some people. That is why it is important to check your blood sugar as you have been advised by your healthcare provider.

Hypoglycemia can happen with:

Hypoglycemia can be mild to severe. Its onset may be rapid. Some patients have few or no warning symptoms, including:

Hypoglycemia may reduce your ability to drive a car or use mechanical equipment and you may risk injury to yourself or others.

Severe hypoglycemia can be dangerous and can cause temporary or permanent harm to your heart or brain. It may cause unconsciousness, seizures, or death.

Symptoms of hypoglycemia may include:

If you have hypoglycemia often or it is hard for you to know if you have the symptoms of hypoglycemia, talk to your healthcare provider.

Mild to moderate hypoglycemia is treated by eating or drinking carbohydrates, such as fruit juice, raisins, sugar candies, milk or glucose tablets. Talk to your healthcare provider about the amount of carbohydrates you should eat to treat mild to moderate hypoglycemia.

Severe hypoglycemia may require the help of another person or emergency medical people. A person with hypoglycemia who is unable to take foods or liquids with sugar by mouth, or is unconscious needs medical help fast and will need treatment with a glucagon injection or glucose given intravenously (IV). Without medical help right away, serious reactions or even death could happen.

Hyperglycemia (high blood sugar):

Hyperglycemia happens when you have too much sugar in your blood. Usually, it means there is not enough insulin to break down the food you eat into energy your body can use. Hyperglycemia can be caused by a fever, an infection, stress, eating more than you should, taking less insulin than prescribed, or it can mean your diabetes is getting worse.

Hyperglycemia can happen with:

Testing your blood or urine often will let you know if you have hyperglycemia. If your tests are often high, tell your healthcare provider so your dose of insulin can be changed.

Hyperglycemia can be mild or severe. Hyperglycemia can progress to diabetic ketoacidosis (DKA) or very high glucose levels (hyperosmolar coma) and result in unconsciousness and death.

Although diabetic ketoacidosis occurs most often in patients with type 1 diabetes, it can also happen in patients with type 2 diabetes who become very sick. Because some patients get few symptoms of hyperglycemia, it is important to check your blood sugar/urine sugar and ketones regularly.

Symptoms of hyperglycemia include:

Symptoms of DKA also include:

Severe or continuing hyperglycemia or DKA needs evaluation and treatment right away by your healthcare provider.

Do not use LANTUS to treat diabetic ketoacidosis.

Other possible side effects of LANTUS include:

Serious allergic reactions:

Some times severe, life-threatening allergic reactions can happen with insulin. If you think you are having a severe allergic reaction, get medical help right away. Signs of insulin allergy include:

Reactions at the injection site:

Injecting insulin can cause the following reactions on the skin at the injection site:

You can reduce the chance of getting an injection site reaction if you change (rotate) the injection site each time. An injection site reaction should clear up in a few days or a few weeks. If injection site reactions do not go away or keep happening, call your healthcare provider.

Tell your healthcare provider if you have any side effects that bother you.

These are not all the side effects of LANTUS. Ask your healthcare provider or pharmacist for more information.

How should I store LANTUS?

General Information about LANTUS

ADDITIONAL INFORMATION

DIABETES FORECAST is a national magazine designed especially for patients with diabetes and their families and is available by subscription from the American Diabetes Association (ADA), P.O.Box 363, Mt. Morris, IL 61054-0363, 1-800-DIABETES (1-800-342-2383). You may also visit the ADA website at www.diabetes.org.

Another publication, COUNTDOWN, is available from the Juvenile Diabetes Research Foundation International (JDRF), 120 Wall Street, 19th Floor, New York, New York 10005, 1-800-JDF-CURE (1-800-533-2873). You may also visit the JDRF website at www.jdf.org.

To get more information about diabetes, check with your healthcare professional or diabetes educator or visit www.DiabetesWatch.com.

Additional information about LANTUS can be obtained by calling 1-800-633-1610 or by visiting www.lantus.com.

Rev. March 2007

sanofi-aventis U.S. LLC
Bridgewater, NJ 08807

©2007 sanofi-aventis U.S. LLC

Patient Information
LANTUS® 3 mL cartridge system (300 units per cartridge system)
100 units per mL (U-100)
(insulin glargine [recombinant DNA origin] injection)

Read this "Patient Information" that comes with LANTUS (LAN-tus) before you start using it and each time you get a refill because there may be new information. This leaflet does not take the place of talking with your healthcare provider about your condition or treatment. If you have questions about LANTUS or about diabetes, talk with your healthcare provider.

What is the most important information I should know about LANTUS?

What is Diabetes?

What is LANTUS?

Who should NOT take LANTUS?

Do not take LANTUS if you are allergic to insulin glargine or any of the inactive ingredients in LANTUS. Check with your healthcare provider if you are not sure.

How should I use LANTUS?

See the "Instructions for OptiClik® Use" section for additional information.

What kind of insulin Pen should I use?

Mixing with LANTUS

Instructions for OptiClik®Use

It is important to read, understand, and follow the step-by-step instructions in the "OptiClik® Instruction Leaflet" before using OptiClik® insulin Pen. Failure to follow the instructions may result in getting too much or too little insulin. If you have lost your leaflet or have a question, go to www.opticlik.com or call 1-800-633-1610.

The following general notes should be taken into consideration before injecting LANTUS:

If your blood glucose reading is high or low, tell your healthcare provider so the dose can be adjusted.

What can affect how much insulin I need?

Illness. Illness may change how much insulin you need. It is a good idea to think ahead and make a "sick day" plan with your healthcare provider in advance so you will be ready when this happens. Be sure to test your blood sugar more often and call your healthcare provider if you are sick.

Medicines. Many medicines can affect your insulin needs. Other medicines, including prescription and non-prescription medicines, vitamins, and herbal supplements, can change the way insulin works. You may need a different dose of insulin when you are taking certain other medicines. Know all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. You may want to keep a list of the medicines you take. You can show this list to your healthcare provider and pharmacists anytime you get a new medicine or refill. Your healthcare provider will tell you if your insulin dose needs to be changed.

Meals. The amount of food you eat can affect your insulin needs. If you eat less food, skip meals, or eat more food than usual, you may need a different dose of insulin. Talk to your healthcare provider if you change your diet so that you know how to adjust your LANTUS and other insulin doses.

Alcohol. Alcohol, including beer and wine, may affect the way LANTUS works and affect your blood sugar levels. Talk to your healthcare provider about drinking alcohol.

Exercise or Activity level. Exercise or activity level may change the way your body uses insulin. Check with your healthcare provider before you start an exercise program because your dose may need to be changed.

Travel. If you travel across time zones, talk with your healthcare provider about how to time your injections. When you travel, wear your medical alert identification. Take extra insulin and supplies with you.

Pregnancy or nursing. The effects of LANTUS on an unborn child or on a nursing baby are unknown. Therefore, tell your healthcare provider if you are planning to have a baby, are pregnant, or nursing a baby. Good control of diabetes is especially important during pregnancy and nursing.

What are the possible side effects of LANTUS and other insulins?

Insulins, including LANTUS, can cause hypoglycemia (low blood sugar), hyperglycemia (high blood sugar), allergy, and skin reactions.

Hypoglycemia (low blood sugar):

Hypoglycemia is often called an "insulin reaction" or "low blood sugar". It may happen when you do not have enough sugar in your blood. Common causes of hypoglycemia are illness, emotional or physical stress, too much insulin, too little food or missed meals, and too much exercise or activity.

Early warning signs of hypoglycemia may be different, less noticeable or not noticeable at all in some people. That is why it is important to check your blood sugar as you have been advised by your healthcare provider.

Hypoglycemia can happen with:

Hypoglycemia can be mild to severe. Its onset may be rapid. Some patients have few or no warning symptoms, including:

Hypoglycemia may reduce your ability to drive a car or use mechanical equipment and you may risk injury to yourself or others.

Severe hypoglycemia can be dangerous and can cause temporary or permanent harm to your heart or brain. It may cause unconsciousness, seizures, or death.

Symptoms of hypoglycemia may include:

If you have hypoglycemia often or it is hard for you to know if you have the symptoms of hypoglycemia, talk to your healthcare provider.

Mild to moderate hypoglycemia is treated by eating or drinking carbohydrates such as fruit juice, raisins, sugar candies, milk or glucose tablets. Talk to your healthcare provider about the amount of carbohydrates you should eat to treat mild to moderate hypoglycemia.

Severe hypoglycemia may require the help of another person or emergency medical people. A person with hypoglycemia who is unable to take foods or liquids with sugar by mouth, or is unconscious needs medical help fast and will need treatment with a glucagon injection or glucose given intravenously (IV). Without medical help right away, serious reactions or even death could happen.

Hyperglycemia (high blood sugar):

Hyperglycemia happens when you have too much sugar in your blood. Usually, it means there is not enough insulin to break down the food you eat into energy your body can use. Hyperglycemia can be caused by a fever, an infection, stress, eating more than you should, taking less insulin than prescribed, or it can mean your diabetes is getting worse.

Hyperglycemia can happen with:

Testing your blood or urine often will let you know if you have hyperglycemia. If your tests are often high, tell your healthcare provider so your dose of insulin can be changed.

Hyperglycemia can be mild or severe. It can progress to diabetic ketoacidosis (DKA) or very high glucose levels (hyperosmolar coma) and result in unconsciousness and death.

Although diabetic ketoacidosis occurs most often in patients with type 1 diabetes, it can also happen in patients with type 2 diabetes who become very sick. Because some patients get few symptoms of hyperglycemia, it is important to check your blood sugar/urine sugar and ketones regularly.

Symptoms of hyperglycemia include:

Symptoms of DKA also include:

Severe or continuing hyperglycemia or DKA needs evaluation and treatment right away by your healthcare provider.

Do not use LANTUS to treat diabetic ketoacidosis.

Other possible side effects of LANTUS include:

Serious allergic reactions:

Some times severe, life-threatening allergic reactions can happen with insulin. If you think you are having a severe allergic reaction, get medical help right away. Signs of insulin allergy include:

Reactions at the injection site:

Injecting insulin can cause the following reactions on the skin at the injection site:

You can reduce the chance of getting an injection site reaction if you change (rotate) the injection site each time. An injection site reaction should clear up in a few days or a few weeks. If injection site reactions do not go away or keep happening call your healthcare provider.

Tell your healthcare provider if you have any side effects that bother you.

These are not all the side effects of LANTUS. Ask your healthcare provider or pharmacist for more information.

How should I store LANTUS?

These storage conditions are summarized in the following table:


Not in-use
(unopened)
Refrigerated		Not in-use
(unopened)
Room Temperature		In-Use
(opened)
(See Temperature Below)
3 mL Cartridge System
Until expiration date
28 days
28 days
Refrigerated or room temperature
3 mL Cartridge System inserted in
OptiClik® insulin Pen

28 days
Room temperature only
(Do not refrigerate)

General Information about LANTUS

ADDITIONAL INFORMATION

DIABETES FORECAST is a national magazine designed especially for patients with diabetes and their families and is available by subscription from the American Diabetes Association (ADA), P.O. Box 363, Mt. Morris, IL 61054-0363, 1-800-DIABETES (1-800-342-2383). You may also visit the ADA website at www.diabetes.org.

Another publication, COUNTDOWN, is available from the Juvenile Diabetes Research Foundation International (JDRF), 120 Wall Street, 19th Floor, New York, New York 10005, 1-800-JDF-CURE (1-800-533-2873). You may also visit the JDRF website at www.jdf.org.

To get more information about diabetes, check with your healthcare professional or diabetes educator or visit www.DiabetesWatch.com.

Additional information about LANTUS can be obtained by calling 1-800-633-1610 or by visiting www.lantus.com.

Rev. March 2007

sanofi-aventis U.S. LLC
Bridgewater, NJ 08807

©2007 sanofi-aventis U.S. LLC

OptiClik® is a registered trademark of sanofi-aventis U.S. LLC
†The brands listed are the trademarks of their respective owners and are not trademarks of sanofi-aventis U.S. LLC


OptiClik®

INSTRUCTION LEAFLET

OptiClik® is a reusable insulin delivery device (insulin Pen) for use with 3 mL Lantus® or Apidra® cartridge (U-100) systems.

OptiClik® allows you to dial the dose in one-unit step increments between one unit and a maximum of 80 units per injection.

OptiClik® is available in different colors. For patients that use two different types of insulin, Lantus or Apidra, it is recommended to use a different color pen for each insulin.

Read these instructions carefully before using your OptiClik®. Read both sides of the leaflet. If you are not able to follow all the instructions completely on your own, use OptiClik® only if you have help from a person who is able to follow the instructions.
Hold the pen as shown in this leaflet. The word "OptiClik" must be readable to the left of the digital dose display to ensure the correct reading of the dose.

If you do not follow these instructions completely, you may get too much or too little insulin.

Keep this leaflet for future reference for each time you use OptiClik®.

You will find further useful information on the back side of this leaflet in the chapters:

(A.)   General Notes (B.)   Troubleshooting (C.)   Storage Instructions (D.)   Other Information

Talk with your healthcare provider before using OptiClik® about proper injection technique. Before using OptiClik®, your healthcare provider should provide training for the use of the pen, or direct you to the appropriate person to get training.

If you have visual problems, use OptiClik® only if you have help from a trained person with good vision.

Additional items needed for use with OptiClik®

If you have any questions about OptiClik® or about diabetes, ask your healthcare professional, go to www.opticlik.com or call sanofi-aventis at 1-800-633-1610.

PRINCIPAL DISPLAY PANEL

LANTUS solution for injection 100 units per mL (U-100)

10 mL vials
image of package label for 100u/mL vial

3 mL cartridge system

image of package label for 100u/mL cartridge


LANTUS 
insulin glargine   injection, solution
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)54868-4626 (0088-2220)
Route of AdministrationSUBCUTANEOUSDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
INSULIN GLARGINE (INSULIN GLARGINE) INSULIN GLARGINE100 [iU]  in 1 mL
Inactive Ingredients
Ingredient NameStrength
ZINC30 ug  in 10 mL
METACRESOL2.7 mg  in 10 mL
POLYSORBATE 2020 mg  in 10 mL
WATER 
HYDROCHLORIC ACID 
SODIUM HYDROXIDE 
Product Characteristics
Color    Score    
ShapeSize
FlavorImprint Code
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
154868-4626-010 mL In 1 VIAL, GLASSNone

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02108106/04/2002

LANTUS 
insulin glargine   injection, solution
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)54868-5765 (0088-2220)
Route of AdministrationSUBCUTANEOUSDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
insulin glargine (insulin glargine) insulin glargine100 [iU]  in 1 mL
Inactive Ingredients
Ingredient NameStrength
ZINC30 ug  in 10 mL
METACRESOL2.7 mg  in 10 mL
POLYSORBATE 2020 mg  in 10 mL
WATER 
HYDROCHLORIC ACID 
SODIUM HYDROXIDE 
Product Characteristics
Color    Score    
ShapeSize
FlavorImprint Code
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
154868-5765-05 CARTRIDGE In 1 CARTONcontains a CARTRIDGE
13 mL In 1 CARTRIDGEThis package is contained within the CARTON (54868-5765-0)

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02108104/04/2007

Labeler - Physicians Total Care, Inc. (194123980)
Establishment
NameAddressID/FEIOperations
Physicians Total Care, Inc.194123980relabel
Revised: 01/2010Physicians Total Care, Inc.