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Brief Summary of Prescribing Information April 2006
Rx Only
LANTUS®
(insulin glargine [rDNA origin] injection)
LANTUS* must NOT be diluted or mixed with any other insulin or solution.
INDICATIONS AND USAGE
LANTUS is indicated for once-dailv subcutaneous administration for the treat
ment 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 antidia
betes 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 pharmaco
kinetic/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 injec
tion 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 dif
ferent 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 hvpoglycemia 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 hypo
glycemia.
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 CLINI
CAL 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 injec
tion 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 general
ized skin reactions, angioedema. bronchospasm, hypotension, or shock and may
be life threatening.
Intercurrent Conditions:
Insulin requirements may be altered during intercurrent conditions such as ill
ness. 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 dis
turbances). 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 profession
al 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 deriv
atives. somatropin. thyroid hormones, estrogens, progestogens (e.g., in oral
contraceptives), protease inhibitors and atypical antipsychotic medications (e.g.
olanzapine and clozapine).
Beta-blockers, donidine. lithium salts, and alcohol may either potentiate or
weaken the blood-glucose-lowering effect of insulin. Pentamidine may cause
hvpoglycemia, which may sometimes be followed by hyperglycemia,
in addition, under the influence of sympatholytic medicinal products such as
beta-blockers, donidine. 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/dav). 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 vehi
cle 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 V 79 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/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 human insulin.
Pregnancy:
Teratogenic Effects: Pregnancy Category C. Subcutaneous reproduction and ter
atology 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 sub
cutaneous starting dose of 10 IU (0.008 mg/kg/day). based on mg/m 2 . 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/m 2 ,
were administered during organogenesis. The effects of insulin glargine did not
generally differ from those observed with regular human insulin in rats or rab
bits. However, in rabbits, five fetuses from two litters of the high-dose group
exhibited dilation of the cerebral ventricles. Fertility and early embryonic devel
opment appeared normal.
There are no well-controlled clinical studies of the use of insulin glargine in preg
nant 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, gener
ally 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 main
tenance 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 fun
dus 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 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 fart 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 observa
tion 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 PRE
CAUTIONS). 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 subcuta
neous 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 naive patients with type 2 diabetes already treat
ed 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 recom
mended 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 hypo
glycemia or hyperglycemia (see PRECAUTIONS. Hypoglycemia).
The dose may also have to be adjusted during intercurrent illness (see PRECAU
TIONS. Intercurrent Conditions).
Brief Summary of Prescribing Information April 2006
sanofi-aventis U.S. LLC
Bridgewater. NJ 08807
Country of Origin Germany
www.lantus.com
© 2006 sanofi-aventis U.S. LLC
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