lantus (insulin glargine)  injection, solution 
[Sanofi-Aventis U.S. LLC ]

LANTUS® must NOT be diluted or mixed with any other insulin or solution.

DESCRIPTION

LANTUS® (insulin glargine [rDNA origin] injection) is a sterile solution of insulin glargine for use as an 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). 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, it is 21A-Gly-30Ba-L-Arg-30Bb-L-Arg-human insulin and has the empirical formula C267H404N72O78S6 and a molecular weight of 6063. It has the following structural formula:

Image from Drug Label Content

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

Inactive ingredients for the 10 mL vial are 30 mcg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, 20 mcg polysorbate 20, and water for injection.

Inactive ingredients for the 3 mL cartridge are 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.

CLINICAL PHARMACOLOGY

Mechanism of Action

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

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, 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 profile allows once-daily dosing as a patient's 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 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 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. 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 human 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 from Drug Label Content

*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 NPH, 78%.

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/or within the same individual.

Pharmacokinetics

Absorption and Bioavailability

After subcutaneous injection of insulin glargine in healthy subjects and in patients with diabetes, the insulin serum concentrations indicated a slower, more prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak in comparison to NPH 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 IU/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 human insulin.

Smoking

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

Pregnancy

The effect of pregnancy on the pharmacokinetics and pharmacodynamics of LANTUS has not been studied (see PRECAUTIONS, Pregnancy).

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.

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 dysfunction (see PRECAUTIONS, Renal Impairment).

Hepatic Impairment

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

Clinical Studies

The safety and effectiveness of insulin glargine given once-daily at bedtime was compared to that of once-daily and twice-daily NPH human insulin in open-label, randomized, active-control, parallel studies of 2327 adult patients and 349 pediatric patients with type 1 diabetes mellitus and 1563 adult patients with type 2 diabetes mellitus (see Tables 1–3). In general, the reduction in glycated hemoglobin (HbA1c) with LANTUS was similar to that with NPH human insulin. The overall rates of hypoglycemia did not differ between patients with diabetes treated to LANTUS compared with NPH human insulin.

Type 1 Diabetes–Adult (see Table 1).

In two large, randomized, controlled clinical studies (Studies A and B), patients with type 1 diabetes (Study A; n=585, Study B; n=534) were randomized to basal-bolus treatment with LANTUS once daily at bedtime or to NPH human insulin once or twice daily and treated for 28 weeks. Regular human insulin was administered before each meal. LANTUS was administered at bedtime. NPH human insulin was administered once daily at bedtime or in the morning and at bedtime when used twice daily. In one large, randomized, controlled clinical study (Study C), patients with type 1 diabetes (n=619) were treated for 16 weeks with a basal-bolus insulin regimen where insulin lispro was used before each meal. LANTUS was administered once daily at bedtime and NPH human insulin was administered once or twice daily. In these studies, LANTUS and NPH human insulin had a similar effect on glycohemoglobin with a similar overall rate of hypoglycemia.

Table 1: Type 1 Diabetes Mellitus–Adult
Study AStudy BStudy C
Treatment duration28 weeks28 weeks16 weeks
Treatment in combination withRegular insulinRegular insulinInsulin lispro
LANTUSNPHLANTUSNPHLANTUSNPH
Number of subjects treated292293264270310309
HbA1c
  Endstudy mean8.138.077.557.497.537.60
  Adj. mean change from baseline+0.21+0.10-0.16-0.21-0.07-0.08
    LANTUS – NPH+0.11+0.05+0.01
    95% CI for Treatment difference(-0.03; +0.24)(-0.08; +0.19)(-0.11; +0.13)
Basal insulin dose
  Endstudy mean19.222.824.831.323.929.2
  Mean change from baseline-1.7-0.3-4.1+1.8-4.5+0.9
Total insulin dose
  Endstudy mean46.751.750.354.847.450.7
  Mean change from baseline-1.1-0.1+0.3+3.7-2.9+0.3
Fasting blood glucose (mg/dL)
  Endstudy mean146.3150.8147.8154.4144.4161.3
  Adj. mean change from baseline-21.1-16.0-20.2-16.9-29.3-11.9

Type 1 Diabetes–Pediatric (see Table 2).

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 human insulin was administered once or twice daily. Similar effects on glycohemoglobin and the incidence of hypoglycemia were observed in both treatment groups.

Table 2: Type 1 Diabetes Mellitus–Pediatric
Study D
Treatment duration28 weeks
Treatment in combination withRegular insulin
LANTUSNPH
Number of subjects treated174175
HbA1c
  Endstudy mean8.919.18
  Adj. mean change from baseline+0.28+0.27
    LANTUS – NPH+0.01
    95% CI for Treatment difference(-0.24; +0.26)
Basal insulin dose
  Endstudy mean18.221.1
  Mean change from baseline-1.3+2.4
Total insulin dose
  Endstudy mean45.046.0
  Mean change from baseline+1.9+3.4
Fasting blood glucose (mg/dL)
  Endstudy mean171.9182.7
  Adj. mean change from baseline-23.2-12.2

Type 2 Diabetes–Adult (see Table 3).

In a large, randomized, controlled clinical study (Study E) (n=570), LANTUS was evaluated for 52 weeks as part of a regimen of combination therapy with insulin and oral antidiabetes agents (a sulfonylurea, metformin, acarbose, or combinations of these drugs). LANTUS administered once daily at bedtime was as effective as NPH human insulin administered once daily at bedtime in reducing glycohemoglobin and fasting glucose. There was a low rate of hypoglycemia that was similar in LANTUS and NPH human insulin treated patients. In a large, randomized, controlled clinical study (Study F), in patients with type 2 diabetes not using oral antidiabetes agents (n=518), a basal-bolus regimen of LANTUS once daily at bedtime or NPH human 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 human insulin in reducing glycohemoglobin and fasting glucose with a similar incidence of hypoglycemia.

Table 3: Type 2 Diabetes Mellitus–Adult
Study EStudy F
Treatment duration52 weeks28 weeks
Treatment in combination withOral agentsRegular insulin
LANTUSNPHLANTUSNPH
Number of subjects treated289281259259
HbA1c
  Endstudy mean8.518.478.147.96
  Adj. mean change from baseline-0.46-0.38-0.41-0.59
    LANTUS – NPH-0.08+0.17
    95% CI for Treatment difference(-0.28; +0.12)(-0.00; +0.35)
Basal insulin dose
  Endstudy mean25.923.642.952.5
  Mean change from baseline+11.5+9.0-1.2+7.0
Total insulin dose
  Endstudy mean25.923.674.380.0
  Mean change from baseline+11.5+9.0+10.0+13.1
Fasting blood glucose (mg/dL)
  Endstudy mean126.9129.4141.5144.5
  Adj. mean change from baseline-49.0-46.3-23.8-21.6

LANTUS Flexible Daily Dosing

The safety and efficacy of LANTUS administered pre-breakfast, pre-dinner, or at bedtime were evaluated in a large, randomized, controlled clinical study, in patients with type 1 diabetes (study G, n=378). Patients were also treated with insulin lispro at mealtime. LANTUS administered at different times of the day resulted in similar reductions in glycated hemoglobin compared to that with bedtime administration (see Table 4). In these patients, data are available from 8-point home glucose monitoring. The maximum mean blood glucose level was observed just prior to injection of LANTUS regardless of time of administration, i.e. pre-breakfast, pre-dinner, or bedtime.

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. Routine monitoring during this trial revealed the following mean changes in systolic blood pressure: pre-breakfast group, 1.9 mm Hg; pre-dinner group, 0.7 mm Hg; pre-bedtime group, -2.0 mm Hg.

The safety and efficacy of LANTUS administered pre-breakfast or at bedtime were also evaluated in a large, randomized, active-controlled clinical study (Study H, n=697) in type 2 diabetes patients no longer adequately controlled on oral agent therapy. All patients in this study also received AMARYL® (glimepiride) 3 mg daily. LANTUS given before breakfast was at least as effective in lowering glycated hemoglobin A1c (HbA1c) as LANTUS given at bedtime or NPH human insulin given at bedtime (see Table 4).

Table 4: Flexible LANTUS Daily Dosing in Type 1 (Study G) and Type 2 (Study H) Diabetes Mellitus
Study GStudy H
Treatmentduration24 weeks24 weeks
Treatment in combination with: Insulin lisproAMARYL® (glimepiride)
LANTUS
Breakfast		LANTUS
Dinner		LANTUS
Bedtime		LANTUS
Breakfast		LANTUS
Bedtime		NPH
Bedtime
*
Intent to treat
†
Not applicable
Number of subjects treated*112124128234226227
HbA1c
  Baseline mean7.567.537.619.139.079.09
  Endstudy mean7.397.427.577.878.128.27
  Mean change from baseline-0.17-0.11-0.04-1.26-0.95-0.83
Basal insulin dose (IU)
  Endstudy mean 27.324.622.840.438.536.8
    Mean change from baseline5.01.81.5
Total insulin dose (IU)NA†NANA
  Endstudy mean53.354.751.5
    Mean change from baseline1.63.02.3

INDICATIONS AND USAGE

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

CONTRAINDICATIONS

LANTUS is contraindicated in patients hypersensitive to insulin glargine or the excipients.

WARNINGS

Hypoglycemia is the most common adverse effect of insulin, including LANTUS. 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 dosing, 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 antidiabetes treatment may need to be adjusted.

PRECAUTIONS

General

LANTUS is not intended for intravenous 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.

LANTUS must NOT be diluted or mixed with any other insulin or solution. If LANTUS 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 and/or 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 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 not known.

As with all insulin preparations, the time course of LANTUS 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.

Hypoglycemia

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

The time of occurrence of hypoglycemia depends on the action profile of the insulins used and may, therefore, change when the treatment regimen or timing of dosing is changed. 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, Changeover to LANTUS).

The prolonged effect of subcutaneous LANTUS may delay recovery from hypoglycemia.

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

Renal Impairment

Although studies have not been performed in patients with diabetes and renal impairment, LANTUS requirements may be diminished because of reduced insulin metabolism, similar to observations found with other insulins (see CLINICAL PHARMACOLOGY, Special Populations).

Hepatic Impairment

Although studies have not been performed in patients with diabetes and hepatic impairment, LANTUS requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism, similar to observations found with other insulins (see CLINICAL PHARMACOLOGY, Special Populations).

Injection Site and Allergic Reactions

As with any insulin therapy, lipodystrophy may occur at the injection site and delay insulin absorption. Other injection site reactions with insulin therapy 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.

Reports of injection site pain were more frequent with LANTUS than NPH human insulin (2.7% insulin glargine versus 0.7% NPH). The reports of pain at the injection site were usually mild and did not result in discontinuation of therapy.

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.

Intercurrent Conditions

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

Information for Patients

LANTUS must only be used if the solution is clear and colorless with no particles visible (see DOSAGE AND ADMINISTRATION, Preparation and Handling).

Patients must be advised that LANTUS must NOT be diluted or mixed with any other insulin or solution (see 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. Refer patients to the LANTUS "Patient Information" circular for additional information.

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

Drug Interactions

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

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

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

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 is for the rat approximately 10 times and for the mouse approximately 5 times the recommended human subcutaneous starting dose of 10 IU (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 is approximately 7 times the recommended human subcutaneous starting dose of 10 IU (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 human insulin.

Pregnancy

Teratogenic Effects

Pregnancy Category C. Subcutaneous reproduction and teratology studies have been performed with insulin glargine and regular human insulin in rats and Himalayan rabbits. The drug 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 IU (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 IU (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 insulin glargine in pregnant women. 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. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

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 is administered to a nursing woman. Lactating women may require adjustments in insulin dose and diet.

Pediatric Use

Safety and effectiveness of LANTUS have been established in the age group 6 to 15 years with type 1 diabetes.

Geriatric Use

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 PRECAUTIONS, Hypoglycemia).

ADVERSE REACTIONS

The adverse events commonly associated with LANTUS include the following:

Body as a whole: allergic reactions (see PRECAUTIONS).

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

Other: hypoglycemia (see WARNINGS and PRECAUTIONS).

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 were usually mild and did not result in discontinuation of therapy. Other treatment-emergent injection site reactions occurred at similar incidences with both insulin glargine and NPH human insulin.

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 and 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 group versus 2.7% in 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.

OVERDOSAGE

An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes long-term 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 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.

DOSAGE AND ADMINISTRATION

LANTUS is a recombinant human insulin analog. Its potency is approximately the same as human insulin. It 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. For patients adjusting timing of dosing with LANTUS, see WARNINGS and PRECAUTIONS, Hypoglycemia. LANTUS is not intended for intravenous administration (see PRECAUTIONS). Intravenous administration of the usual subcutaneous dose could result in severe hypoglycemia. The desired blood glucose levels as well as the doses and timing of antidiabetes medications must be determined individually. Blood glucose monitoring is recommended for all patients with diabetes. The prolonged duration of activity of LANTUS is dependent on injection into subcutaneous space.

As with all insulins, injection sites within an injection area (abdomen, thigh, or deltoid) must be rotated from one injection to the next.

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.

LANTUS is not the insulin of choice for the treatment of diabetes ketoacidosis. Intravenous short-acting insulin is the preferred treatment.

Pediatric Use

LANTUS can be safely administered to pediatric patients ≥6 years of age. Administration to pediatric patients <6 years has not been studied. Based on the results of a study in pediatric patients, the dose recommendation for changeover to LANTUS is the same as described for adults in DOSAGE AND ADMINISTRATION, Changeover to LANTUS.

Initiation of LANTUS Therapy

In a clinical study with insulin naïve patients with type 2 diabetes already treated with oral antidiabetes drugs, LANTUS was started at an average dose of 10 IU once daily, and subsequently adjusted according to the patient's need to a total daily dose ranging from 2 to 100 IU.

Changeover to LANTUS

If changing from a treatment regimen with an intermediate- or long-acting insulin to a regimen with LANTUS, the amount and timing of short-acting insulin or fast-acting insulin analog or the dose of any oral antidiabetes drug may need to be adjusted. In clinical studies, when patients were transferred from once-daily NPH human insulin or ultralente human insulin to once-daily LANTUS, the initial dose was usually not changed. However, when patients were transferred from twice-daily NPH human insulin to LANTUS once daily, to reduce the risk of hypoglycemia, the initial dose (IU) was usually reduced by approximately 20% (compared to total daily IU of NPH human insulin) and then adjusted based on patient response (see PRECAUTIONS, Hypoglycemia).

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 analog 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 analogs. Dose adjustment of LANTUS and other insulins or oral antidiabetes drugs may be required; for example, if the patient's timing of dosing, weight or lifestyle changes, or other circumstances arise that increase susceptibility to hypoglycemia or hyperglycemia (see PRECAUTIONS, Hypoglycemia).

The dose may also have to be adjusted during intercurrent illness (see PRECAUTIONS, Intercurrent Conditions).

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 PRECAUTIONS, General).

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

Cartridge system: If OptiClik®, the Insulin Delivery Device for LANTUS, malfunctions, LANTUS may be drawn from the cartridge system into a U-100 syringe and injected.

HOW SUPPLIED

LANTUS 100 units per mL (U-100) is available in the following package size:

10 mL vials (NDC 0088-2220-33)

3 mL cartridge system1, package of 5 (NDC 0088-2220-52)

1
Cartridge systems are for use only in OptiClik® (Insulin Delivery Device)

Storage

Unopened Vial/Cartridge system

Unopened LANTUS vials and cartridge systems should be stored in a refrigerator, 36°F – 46°F (2°C – 8°C). LANTUS should not be stored in the freezer and it should not be allowed to freeze.

Discard if it has been frozen.

Open (In-Use) Vial/Cartridge system

Opened vials, whether or not refrigerated, must be used within 28 days after the first use. They must be discarded if not used within 28 days. 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).

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® kept at room temperature must be discarded after 28 days. Do not store OptiClik®, with or without cartridge system, in a refrigerator at any time.

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

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)
10 mL Vial Until expiration date28 days28 days
Refrigerated or room temperature
3 mL Cartridge systemUntil expiration date28 days28 days
Refrigerated or room temperature
3 mL Cartridge
system inserted into OptiClik®		28 days
Room temperature only
(Do not refrigerate)

Rev. April 2006
Manufactured for an distributed by:
sanofi-aventis U.S. LLC
Bridgewater NJ 08807

Made in Germany
www.lantus.com

© 2006 sanofi-aventis U.S. LLC

OptiClik® is a registered trademark of sanofi-aventis U.S. LLC, Bridgewater NJ 08807

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 from Drug Label Content

  4. Wipe the top of the vial with an alcohol swab. You do not have to shake the vial of LANTUS before use.

    Image from Drug Label Content

  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 from Drug Label Content                  Image from Drug Label Content

  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 from Drug Label Content

  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 from Drug Label Content

  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 from Drug Label Content

  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 from Drug Label Content

  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 ideato 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. January 2006
Aventis Pharmaceuticals Inc.
Kansas City, MO 64137 USA
a member of the sanofi-aventis Group, Bridgewater NJ 08807

©2006 Aventis Pharmaceuticals Inc.

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 importantduring 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 SystemUntil expiration date28 days28 days
Refrigerated or room temperature
3 mL cartridge system inserted in OptiClik® insulin Pen28 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. January 2006
Aventis Pharmaceuticals Inc.
Kansas City, MO 64137 USA
a member of the sanofi-aventis Group, Bridgewater NJ 08807

©2006 Aventis Pharmaceuticals Inc.

OptiClik® is a registered trademark of Aventis Pharmaceuticals Inc., a member of the sanofi-aventis Group, Bridgewater NJ 08807

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.

Image from Drug Label Content

General Warnings and Precautions

This pen is only for your use. Do not share it with anyone else.

Insulin

Check the label on your Cartridge System to make sure you have the correct insulin before injecting. Using the wrong insulin may result in unwanted changes in blood sugar that could be harmful to your health.

Needles

You must use a new sterile needle (intact protective seal) for each injection. This prevents a blocked needle and air bubbles. In order to avoid injuries, replace Outer Needle Cap before removing and disposing of used needles.

Safety test

Before each injection, carry out the Safety Test (Step Image from Drug Label Content). If you do not follow the instructions completely, you may get too much or too little insulin. Injecting too much or too little insulin dose may lead to unwanted blood sugar changes (see the package leaflet for your insulin). Do not perform the safety test without the needle attached.

Damage to OptiClik®

OptiClik® may become damaged by rough handling, dropping, or turning of the Dosage Knob by force. Make sure that no dirt gets in contact with the mechanical parts. You should always make sure that:

a)
The Cartridge System is undamaged.
b)
The Start Button, Dosage Knob, and Digital Dose Display operate properly.

Do not use tools on OptiClik®. If you are not sure whether or not your OptiClik® is damaged, contact your healthcare professional or call 1-800-633-1610. If damaged, it is no longer safe to use. In an emergency, you can draw up the insulin from the Cartridge System using a U-100 insulin syringe.

OptiClik® should not be used near electrical and electronic equipment.

Step 1: Inserting the Cartridge System

Do not shake the Cartridge System before use. You should look at the solution in the Cartridge System before inserting it into OptiClik®. If the solution is cloudy, slightly colored, or has particles in it, do not use the Cartridge System.

Image from Drug Label Content

A
Make sure the Dosage Knob is pushed in.

Image from Drug Label ContentImage from Drug Label Content

B
Hold the Pen Body with the release button facing up. Insert the Cartridge System straight into the Pen Body. If you meet resistance, slightly raise and rotate the Cartridge System while inserting it. Make sure that it clicks in. Do not use force.

Image from Drug Label Content

C
To make sure that the Cartridge System clicked in place properly, gently try pulling out the Cartridge System. The Cartridge System should not come out. Make sure you do not press the Cartridge Release button during or after this check.

OptiClik® is now ready for Step 2 (Attaching the needle), or it can be stored with the attached Pen Cap.

DO NOT STORE YOUR OPTICLIK® IN A REFRIGERATOR AFTER CARTRIDGE SYSTEM IS INSERTED IN OPTICLIK®

Step 2: Attaching the needle

Image from Drug Label Content

A
Peel off the Protective Seal on the needle.

Image from Drug Label Content

Image from Drug Label Content

B
Use an alcohol swab to wipe the rubber seal on the end of the Cartridge System. Attach a new needle straight to the Cartridge System and screw into place without removing the Outer and Inner Needle Caps

Image from Drug Label Content

C
Remove Outer Needle Cap from the needle.
Save Outer Needle Cap for use later on in discarding the needle.

Step 3: Safety Test

Before each injection, carry out the Safety Test or you may get too much or too little insulin.

Make sure a needle is attached to OptiClik® before you do the Safety Test. Do not press the Cartridge Release Button during these steps.

Image from Drug Label Content

A
Press the Start Button.

Image from Drug Label Content

B
The Dosage Knob must come out. "00" appears in the Digital Dose Display.

Image from Drug Label Content

C
Turn the Dosage Knob to the right (clockwise) until it clicks. "01" appears in the Digital Dose Display.

Image from Drug Label Content

D
Remove and discard the Inner Needle Cap. Handle the exposed needle carefully.

Image from Drug Label Content

E
Hold OptiClik® with the needle pointing up.

Press the Dosage Knob fully until it stays in.

Insulin must appear at the tip of the needle. If not, repeat the Safety Test. When replacing an empty cartridge system with a new one, it might require repeating this procedure several times.

A Safety Test must be carried out before each injection.

Additional information about "Cartridge System" and "Removing air bubbles" is on the back side of this leaflet.

Step 4: Setting the dose

Image from Drug Label Content

A
Press the Start Button.

Image from Drug Label Content

B
Turn the Dosage Knob slowly to the right (clockwise) until you reach your required dose. Make sure that the dosage knob is not in between two dose steps. You must feel and hear a click. If you have selected a dose that is too high, simply turn the Dosage Knob back (to the left). If you have dialed past 80 units, see (B.) TROUBLESHOOTING, Dose-setting on the back of this leaflet.

Step 5: Injecting the dose

Image from Drug Label Content

A
Check the label on your cartridge system to make sure you have the correct insulin before injecting. Clean the injection area with alcohol. Insert the needle as recommended by your healthcare professional (e.g., lightly pinch a fold of skin on your upper arm, stomach, or thigh. Insert the needle straight into the pinched skin).

Image from Drug Label Content

B
Press the Dosage Knob slowly and completely. Slowly count to 10 while holding the Dosage Knob in before withdrawing the needle.The Dosage Knob must stay in. The Dosage Knob staying in after injection indicates the delivery of the full dose.
After injecting your dose, the Digital Dose Display will not go back to "0" but will show the delivered dose for 2 minutes. Do not re-inject your dose as this may result in an overdose.

Do not press the Cartridge Release Button or the Start Button while injecting.

Step 6: Removing the needle

Image from Drug Label Content

A
Replace Outer Needle Cap carefully.

Image from Drug Label Content

B
Remove the needle after the injection. For safe disposal of needles see (A.) GENERAL NOTES, Needles for OptiClik® on the back of this leaflet. Always replace Pen Cap on the Pen Body after use.

OptiClik® can be stored with the attached Cartridge System until your next injection. See (C.) STORAGE INSTRUCTIONS.

Step 7: Replacing an empty Cartridge System

Image from Drug Label Content

A
Make sure the Dosage Knob is pushed in.

Image from Drug Label Content

B
Press the Cartridge Release Button, and remove the entire Cartridge System. Dispose of the Cartridge System.

Start again at Step 1 (Inserting the Cartridge System).

Image from Drug Label Content

A. GENERAL NOTES

Cartridge System

The Cartridge System is sold separately. Before every injection, check the appearance of the solution in the Cartridge System and follow the instructions in the "Patient Information" leaflet for the insulin. It is important to follow the directions of this Instruction Leaflet closely to help avoid side effects (e.g., infections, improper dosing). Consult with your healthcare professional before using OptiClik®.

Before the use of an unopened, refrigerated Cartridge System, take it out of the refrigerator and leave it at room temperature for about 1 to 2 hours. Do not remove the Cartridge System from packaging until ready to use. This will prevent dust or dirt from getting into the mechanical parts of the Cartridge System. Use an alcohol swab to wipe the rubber seal on the end of the Cartridge System before inserting the needle. Do not open or manipulate the Cartridge System in any way.

Needles for OptiClik®

BD Ultra-Fine needles are available from BD Consumer Healthcare. Contact your healthcare professional for further information.

Needles may vary from country to country and may not be interchangeable. If you intend to travel abroad, make sure that you have sufficient needles and insulin with you.

Never store OptiClik® with a needle attached. Storing OptiClik® with the needle attached may allow insulin to leak from OptiClik® and air bubbles to form in the Cartridge System. Used needles 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.

Removing air bubbles

Air bubbles must be removed before each injection during the Safety Test (Step 3 for Safety Test). If air bubbles still remain, repeat the Safety Test, turning the Dosage Knob to the right until "02" appears on the display. Gently tap the Cartridge System until the air rises to the top of the Cartridge System tip. Then press the Dosage Knob until it stays in. If necessary, keep repeating the Safety Test until insulin appears at the tip of the needle.

Setting the dose and Display feature

TTo read the dose correctly, hold OptiClik® as shown in Step 4B, Setting the dose. The printed “OptiClik” must be readable left of the dose display. Do not hold the pen upside down when reading the dose display; otherwise you may misread the dose on the Digital Dose Display.
The Digital Dose Display shows the delivered dose for 2 minutes after every injection and then turns off to conserve battery power. With the Dosage Knob released the display also switches off after 2 minutes.

How long will OptiClik® last

The expected lifetime of OptiClik® is 3 years.

Image from Drug Label Content flashes when the Start Button is pressed:

OptiClik® is reaching the end of its expected lifetime (3 years). The Digital Dose Display will continue to operate for about 4 more weeks. Please obtain a new OptiClik®.

Image from Drug Label Content stays when the Start Button is pressed:

OptiClik® has reached the end of its lifetime. When you continue to turn the Dosage Knob, the display still shows Image from Drug Label Content. Please obtain a new OptiClik®.

B. TROUBLESHOOTING

Safety test

No insulin appears at the needle tip during Step 3 (Safety Test):

Repeat Step 3 (Safety Test). If no insulin appears this time either, confirm that:

  1. The needle is firmly in position. Replace a blocked or defective needle with a new one.
  2. The Dosage Knob has been set correctly (always turn the Dosage Knob to the right/clockwise to preselect the dose).
    Turn the Dosage Knob one click to the right, equal to one unit.
  3. The Cartridge System has been inserted correctly. Check by trying to pull the Cartridge System gently out. If the Cartridge System comes out, reinsert it completely, see Step 1 (Inserting the Cartridge System). Repeat Step 3 (Safety Test).
  4. The Cartridge System is not empty. If it is empty, insert a new one. Repeat Step 3 (Safety Test).

You hear no clicking sound during dose-setting:

The Cartridge System may have been inserted incorrectly. Check by trying to pull the Cartridge System gently out. If the Cartridge System comes out, reinsert it completely, see Step 1 (Inserting the Cartridge System). Repeat Step 3 (Safety Test).

If you still hear no clicking sound, try a new Cartridge System and listen for clicking sound. If there is still no clicking sound, obtain a new OptiClik®.

Dose-setting

Insulin drips from the needle tip during dose-setting:

The maximum dose of OptiClik® is 80 units. If you continue to dial after reaching 80 units, insulin will drip from the needle and the display will continue to show "80". In such a case, DO NOT turn back to the required dose, instead dial back (to the left) to "00". Press the Dosage Knob to expel excess insulin and to reset OptiClik®. OptiClik® is now again ready for dose setting. If you need a dose greater than 80 units, you should give it as more than one injection.

You feel resistance during dose-setting and the Dosage Knob will not turn further forward (to the right):

a)
You are turning to the left and trying to dial down below zero. Turn the Dosage Knob to the right to dial your dose.
b)
The Cartridge System is almost empty and no longer contains a sufficient amount of insulin for the dose you need. For example, if there are only 20 units left in the Cartridge System and you need 25 units, the dosage knob will stop at 20 units. You can choose to do one of the following:
1)
Do not force the Dosage Knob any further (to the right). Inject the partial dose (20 units in the example), and replace the empty Cartridge System with a new one. Perform the Safety Test as described in Step 3, then inject the remainder of the dose to equal your total prescribed dose. In the above example, the remaining dose is 5 units.
OR
2)
Dial back (to the left) to "00". Follow Step 7 (Replacing an empty Cartridge System), Step 1 (Inserting the Cartridge System), Step 2 (Attaching the needle), and Step 3 (Safety Test).
c)
You have dialed (to the right) past the maximum dose of 80 units and have no needle (or a clogged needle) mounted. Dial completely back (to the left) to "00", and perform Step 2 (Attaching the needle) and Step 3 (Safety Test). Do not force the Dosage Knob to turn further.

The Dosage Knob does not stop at "00":

When turned back completely, the Dosage Knob should stop at "00", however, sometimes it may stop at "02" or "01". Make sure that a needle is attached; then press the Dosage Knob down (insulin will appear at the tip of the needle). OptiClik® is now ready for dose setting.

The Dosage Knob no longer turns after a new Cartridge System has been inserted:

Check that the Cartridge System is firmly clicked in. Reseat the Cartridge System and try again. If it still does not work, try again with a new Cartridge System, see Step 1 (Inserting the Cartridge System). Otherwise, get a new OptiClik®.

The Dosage Knob does not come out after you pressed the Start Button:

Do not pull out the Dosage Knob. Check that the Cartridge System is firmly clicked in, see Step 1B-Inserting the Cartridge System.

Insulin injection

The Dosage Knob cannot be pressed down for the insulin injection or it does not stay down:

  1. In setting the dose, you have turned the Dosage Knob so that it is between two dose steps.
    Turn the Dosage Knob to the right or the left to the desired dose.
  2. The needle may be blocked or defective. Use a new needle.
  3. Avoid pushing the Start Button and Dosage Knob at the same time.

After withdrawing the needle from your skin, more than one drop of insulin drips from the needle:

It is possible that you may not have injected your full insulin dose. DO NOT try to make up for the shortfall in your insulin dose by giving a second injection (otherwise you will be at risk for low blood sugar).

Please check your blood sugar and consult with your healthcare professional.

You can avoid the problem next time by taking the following steps:

  1. Remove any air bubbles that may be present in the Cartridge System
    (see "GENERAL NOTES: Removing air bubbles").
  2. After delivering the insulin dose, slowly count to 10 before withdrawing the needle from your skin.

Cartridge System replacement

The Cartridge System and Pen Body do not click back together properly:

  1. Check that the Dosage Knob is pushed in.
  2. Check that you have put the Cartridge System correctly into the Pen Body. Take the Cartridge System out and insert it again (see under Step 7 for replacing an empty Cartridge System and Step 1 for inserting the Cartridge System). Repeat Step 2 for attaching the needle and Step 3 for Safety Test.

Digital Dose Display functions

Image from Drug Label Content is displayed:

The Dosage Knob has been forced into the negative range with excessive force. The Cartridge System might be damaged and needs to be replaced. Follow the instructions under Step 7 to replace the Cartridge System and dispose of the damaged Cartridge System. Repeat Step 1 for inserting the Cartridge System, Step 2 for attaching the needle, and Step 3 for Safety Test.

Image from Drug Label Content and Image from Drug Label Content flash alternately:

a)
The Dosage Knob has been forced into the negative range and was pushed in. The Cartridge System might be damaged and needs to be replaced. Repeat Step 7 for replacing an empty Cartridge System and dispose of the damaged Cartridge System. Repeat Step 1 for inserting the Cartridge System, Step 2 for attaching the needle, and Step 3 for Safety Test.
b)
The Dosage Knob has been turned too quickly. You can choose to do one of the following:
1)
Dispose of the unknown pre-set dose by pressing the Dosage Knob. Set your dose (Step 4) and inject your dose (Step 5). OR
2)
Turn the Dosage Knob slowly backward (to the left) until it stops, and then push the Dosage Knob in. Restart OptiClik® and dial your dose.

No numbers appear on the Digital Dose Display when the Start Button is pressed or when the Dosage Knob is released:

Press the Dosage Knob. Start with a Safety Test (Step 3).

If there are still no numbers on Digital Dose Display, you should obtain a new OptiClik®.

The Digital Dose Display goes blank during dose setting (e.g., if you are interrupted in the middle of your injection preparations):

The energy save function has automatically come into operation. Turn the Dosage Knob one click further (to the right). OptiClik® should now be ready to use again; check the Digital Dose Display and adjust for the right dose if needed.

Battery Information

Image from Drug Label Content flashes when the Start Button is pressed:

Your battery is running out. Please obtain a new OptiClik® as soon as possible.

Image from Drug Label Content is displayed when the Start Button is pressed:

Your battery has run out. Please obtain a new OptiClik®.

C. STORAGE INSTRUCTIONS

Always store OptiClik® Pen Body at room temperature below 86°F (30°C). Do not store OptiClik®, (with or without the Cartridge System inserted), in a refrigerator at any time. Protect OptiClik® from moisture and direct heat. When OptiClik® is not in use, push the Dosage Knob in to conserve the battery and to ensure OptiClik® functions throughout its expected lifetime.

To avoid dust or dirt from getting into OptiClik®, always replace the Pen Cap.

Once the Cartridge System is used with OptiClik®, the Cartridge System can be used for up to 28 days under normal carrying conditions (for Lantus®, below 86°F [30°C]; for Apidra®, below 77°F [25°C]). For specific insulin storage information, see "Patient Information" for Lantus® or Apidra® 3 mL Cartridge System.

Do not store OptiClik® with the needle attached to the Cartridge System.

D. OTHER INFORMATION

Care, cleaning, and maintenance instructions

Handle OptiClik® carefully. To keep it clean, use a clean damp cloth. Clean it once a week. Dirt can impede the operation. DO NOT use cleaning agents. Use an alcohol swab only for cleaning the Cartridge System's rubber seal.

Lifetime

OptiClik® has a lifetime of 3 years. See "(A.) GENERAL NOTES, How long will OptiClik® last" for details.

Manufactured for and distributed by:

sanofi-aventis U.S. LLC
Bridgewater NJ 08807

OptiClik®, Lantus® and Apidra® are registered trademarks of sanofi-aventis U.S. LLC.

For more information call toll free 1-800-633-1610 or visit www.opticlik.com

Date of revision:
December 2006

Image from Drug Label Content


Lantus (insulin glargine)
PRODUCT INFO
Product Code0088-2220Dosage FormINJECTION, SOLUTION
Route Of AdministrationSUBCUTANEOUSDEA Schedule
INGREDIENTS
Name (Active Moiety)TypeStrength
insulin glargine (insulin glargine) Active100 UNITS  In 1 MILLILITER
zincInactive30 MICROGRAM  In 10 MILLILITER
m-cresolInactive2.7 MILLIGRAM  In 10 MILLILITER
glycerol 85%Inactive20 MILLIGRAM  In 10 MILLILITER
polysorbate 20Inactive20 MICROGRAM  In 10 MILLILITER
waterInactive 
hydrochloric acidInactive 
sodium hydroxideInactive 
IMPRINT INFORMATION
CharacteristicAppearanceCharacteristicAppearance
ColorScore
ShapeSymbol
Imprint CodeCoating
Size
PACKAGING
#NDCPackage DescriptionMultilevel Packaging
10088-2220-3310 MILLILITER In 1 VIAL, GLASSNone
20088-2220-525 CARTRIDGE In 1 CARTONcontains a CARTRIDGE
23 MILLILITER In 1 CARTRIDGEThis package is contained within the CARTON (0088-2220-52)

Revised: 02/2007