Lantus Warnings From Their Website

[Guest guest]

http://www.aventis-us.com/PIs/lantus_TXT.html#Warnings

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

Information for the Patient 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).

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).