Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3653
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Lantus (Injection, Solution)
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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 . Intravenous administration
of the usual subcutaneous dose could result in severe hypoglycemia.
The desired blood glucose levels as wellas 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.<br/>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.<br/>Initiation of LANTUS Therapy: In a clinical study
with insulin na��ve 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.<br/>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 fromtwice-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).<br/>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 . 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.
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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. . 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 21-Gly-30a-L-Arg-30b-L-Arg-human insulin and has the empirical
formula CHNOSand a molecular weight of 6063. It has the following
structural formula: 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.
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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.<br/>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 type1 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 *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.<br/>Pharmacokinetics:<br/>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.<br/>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 (21-Gly-insulin) and M2 (21-Gly-des-30-Thr-insulin). Unchanged drug and these degradation
products are also present in the circulation.<br/>Special Populations:<br/>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.<br/>Smoking: The effect
of smoking on the pharmacokinetics/pharmacodynamics of LANTUS has
not been studied.<br/>Pregnancy: The effect
of pregnancy on the pharmacokinetics and pharmacodynamics of LANTUS
has not been studied (see PRECAUTIONS,
Pregnancy).<br/>Obesity: In controlled
clinical trials, which included patients with Body Mass Index (BMI)
up to and including 49.6 kg/m, subgroup analyses based
on BMI did not show any differences in safety and efficacy between
insulin glargine and NPH human insulin.<br/>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 .<br/>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 .<br/>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.<br/>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.<br/>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.<br/>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 wassimilar 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.<br/>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.
LANTUSgiven 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).
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LANTUS is contraindicated
in patients hypersensitive to insulin glargine or the excipients.
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LANTUS 100 units per mL
(U-100) is available in the following package size: 10 mL vials (NDC 0088-2220-33) 3 mL cartridge system,
package of 5 (NDC 0088-2220-52)<br/>Storage:<br/>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.<br/>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:
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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.
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insulin glargine
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Lantus (Injection, Solution)
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The adverse events commonly
associated with LANTUS include the following: Body as a
whole: allergic reactions . Skin and appendages: injection site reaction, lipodystrophy, pruritus, rash . Other: hypoglycemia . 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 observedin other clinical studies.
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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.
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Lantus
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