Lantus SoloSTAR Quick Reference Manual - page 15
Nevertheless, caution should be exercised when LANTUS is administered to geriatric patients. In
elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be
conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly
[See Warnings and Precautions (5.3)].
10.
OVERDOSAGE
An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and
sometimes prolonged and life-threatening hypoglycemia. Mild episodes of hypoglycemia can usually
be treated with oral carbohydrates. Adjustments in drug dosage, meal patterns, or exercise may be
needed.
More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated
with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. After apparent clinical
recovery from hypoglycemia, continued observation and additional carbohydrate intake may be
necessary to avoid recurrence of hypoglycemia.
11.
DESCRIPTION
LANTUS (insulin glargine [rDNA origin] injection) is a sterile solution of insulin glargine for use as a
subcutaneous injection. Insulin glargine is a recombinant human insulin analog that is a long-acting (up
to 24-hour duration of action), parenteral blood-glucose-lowering agent [See Clinical Pharmacology
(12)]. LANTUS is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain
of Escherichia coli (K12) as the production organism. Insulin glargine differs from human insulin in that
the amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the
C-terminus of the B-chain. Chemically, insulin glargine is 21
A
-Gly-30
B
a-L-Arg-30
B
b-L-Arg-human insulin
and has the empirical formula C
267
H
404
N
72
O
78
S
6
and a molecular weight of 6063. Insulin glargine 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 Units (3.6378 mg) insulin glargine.
The 10 mL vial presentation contains the following inactive ingredients per mL: 30 mcg zinc, 2.7 mg
m-cresol, 20 mg glycerol 85%, 20 mcg polysorbate 20, and water for injection.
The 3 mL cartridge presentation contains the following inactive ingredients per mL: 30 mcg zinc, 2.7
mg m-cresol, 20 mg glycerol 85%, and water for injection.
The pH is adjusted by addition of aqueous solutions of hydrochloric acid and sodium hydroxide.
LANTUS has a pH of approximately 4.
12.
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin
and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal
muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis,
and enhances protein synthesis.
12.2 Pharmacodynamics
Insulin glargine is a human insulin analog that has been designed to have low aqueous solubility at
neutral pH. At pH 4, as in the LANTUS injection solution, insulin glargine is completely soluble. After
injection into the subcutaneous tissue, the acidic solution is neutralized, leading to formation of
microprecipitates from which small amounts of insulin glargine are slowly released, resulting in a
relatively constant concentration/time profile over 24 hours with no pronounced peak. This profile allows
once-daily dosing as a basal insulin.
In clinical studies, the glucose-lowering effect on a molar basis (i.e., when given at the same doses)
of intravenous insulin glargine is approximately the same as that for human insulin. In euglycemic clamp
studies in healthy subjects or in patients with type 1 diabetes, the onset of action of subcutaneous
insulin glargine was slower than NPH insulin. The effect profile of insulin glargine was relatively constant
with no pronounced peak and the duration of its effect was prolonged compared to NPH insulin. Figure
1 shows results from a study in patients with type 1 diabetes conducted for a maximum of 24 hours
after the injection. The median time between injection and the end of pharmacological effect was 14.5
hours (range: 9.5 to 19.3 hours) for NPH insulin, and 24 hours (range: 10.8 to
>24.0 hours) (24 hours
was the end of the observation period) for insulin glargine.
Figure 1. Activity Profile in Patients with Type 1 Diabetes
* Determined as amount of glucose infused to maintain constant plasma glucose levels (hourly mean
values); indicative of insulin activity.
The longer duration of action (up to 24 hours) of LANTUS is directly related to its slower rate of
absorption and supports once-daily subcutaneous administration. The time course of action of insulins,
including LANTUS, may vary between individuals and within the same individual.
12.3 Pharmacokinetics
Absorption and Bioavailability. After subcutaneous injection of insulin glargine in healthy subjects and
in patients with diabetes, the insulin serum concentrations indicated a slower, more prolonged
absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak
in comparison to NPH insulin. Serum insulin concentrations were thus consistent with the time profile
of the pharmacodynamic activity of insulin glargine.
After subcutaneous injection of 0.3 Units/kg insulin glargine in patients with type 1 diabetes, a relatively
constant concentration/time profile has been demonstrated. The duration of action after abdominal,
deltoid, or thigh subcutaneous administration was similar.
Metabolism. A metabolism study in humans indicates that insulin glargine is partly metabolized at the
carboxyl terminus of the B chain in the subcutaneous depot to form two active metabolites with in vitro
activity similar to that of insulin, M1 (21
A
-Gly-insulin) and M2 (21
A
-Gly-des-30
B
-Thr-insulin). Unchanged
drug and these degradation products are also present in the circulation.
Special Populations
Age, Race, and Gender. Information on the effect of age, race, and gender on the pharmacokinetics
of LANTUS is not available. However, in controlled clinical trials in adults (n=3890) and a controlled
clinical trial in pediatric patients (n=349), subgroup analyses based on age, race, and gender did not
show differences in safety and efficacy between insulin glargine and NPH insulin [see Clinical Studies
(14)].
Smoking. The effect of smoking on the pharmacokinetics/pharmacodynamics of LANTUS has not been
studied.
Pregnancy. The effect of pregnancy on the pharmacokinetics and pharmacodynamics of LANTUS has
not been studied [see Use in Specific Populations (8.1)].
Obesity. In controlled clinical trials, which included patients with Body Mass Index (BMI) up to and
including 49.6 kg/m
2
, subgroup analyses based on BMI did not show differences in safety and efficacy
between insulin glargine and NPH insulin [see Clinical Studies (14)].
Renal Impairment. The effect of renal impairment on the pharmacokinetics of LANTUS has not been
studied. However, some studies with human insulin have shown increased circulating levels of insulin
in patients with renal failure. Careful glucose monitoring and dose adjustments of insulin, including
LANTUS, may be necessary in patients with renal impairment [See Warnings and Precautions (5.5)].
Hepatic Impairment. The effect of hepatic impairment on the pharmacokinetics of LANTUS has not
been studied. However, some studies with human insulin have shown increased circulating levels of
insulin in patients with liver failure. Careful glucose monitoring and dose adjustments of insulin,
including LANTUS, may be necessary in patients with hepatic impairment [See Warnings and
Precautions (5.6)].
13.
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In mice and rats, standard two-year carcinogenicity studies with insulin glargine were performed at
doses up to 0.455 mg/kg, which was for the rat approximately 10 times and for the mouse
approximately 5 times the recommended human subcutaneous starting dose of 10 Units/day (0.008
mg/kg/day), based on mg/m
2
. The findings in female mice were not conclusive due to excessive
mortality in all dose groups during the study. Histiocytomas were found at injection sites in male rats
(statistically significant) and male mice (not statistically significant) in acid vehicle containing groups.
These tumors were not found in female animals, in saline control, or insulin comparator groups using
a different vehicle. The relevance of these findings to humans is unknown.
Insulin glargine was not mutagenic in tests for detection of gene mutations in bacteria and mammalian
cells (Ames- and HGPRT-test) and in tests for detection of chromosomal aberrations (cytogenetics in
vitro in V79 cells and in vivo in Chinese hamsters).
In a combined fertility and prenatal and postnatal study in male and female rats at subcutaneous doses
up to 0.36 mg/kg/day, which was approximately 7 times the recommended human subcutaneous
starting dose of 10 Units/day (0.008 mg/kg/day), based on mg/m
2
, maternal toxicity due to dose-
dependent hypoglycemia, including some deaths, was observed. Consequently, a reduction of the
rearing rate occurred in the high-dose group only. Similar effects were observed with NPH insulin.
14.
CLINICAL STUDIES
The safety and effectiveness of LANTUS given once-daily at bedtime was compared to that of
once-daily and twice-daily NPH insulin in open-label, randomized, active-controlled, parallel studies of
2,327 adult patients and 349 pediatric patients with type 1 diabetes mellitus and 1,563 adult patients
with type 2 diabetes mellitus (see Tables 8–11). In general, the reduction in glycated hemoglobin
(HbA1c) with LANTUS was similar to that with NPH insulin. The overall rates of hypoglycemia did not
differ between patients with diabetes treated with LANTUS compared to NPH insulin [See Adverse
Reactions (6.1)].
Type 1 Diabetes–Adult (see Table 8).
In two clinical studies (Studies A and B), patients with type 1 diabetes (Study A; n=585, Study B; n=534)
were randomized to 28 weeks of basal-bolus treatment with LANTUS or NPH insulin. Regular human
insulin was administered before each meal. LANTUS was administered at bedtime. NPH insulin was
administered once daily at bedtime or in the morning and at bedtime when used twice daily.
In another clinical study (Study C), patients with type 1 diabetes (n=619) were randomized to 16 weeks
of basal-bolus treatment with LANTUS or NPH insulin. Insulin lispro was used before each meal.
LANTUS was administered once daily at bedtime and NPH insulin was administered once or twice daily.
In these 3 studies, LANTUS and NPH insulin had similar effects on HbA1c (Table 8) with a similar
overall rate of hypoglycemia [See Adverse Reactions (6.1)].
Table 8: Type 1 Diabetes Mellitus–Adult
Study A
Study B
Study C
Treatment duration
Treatment in
combination with
28 weeks
Regular insulin
28 weeks
Regular insulin
16 weeks
Insulin lispro
LANTUS
NPH
LANTUS
NPH
LANTUS
NPH
Number of subjects
treated
292
293
264
270
310
309
4
Lantus PI.April.2010