Lantus (Insulin Glargine) - Warnings and Precautions

/Home/Diabetes Treatment/Diabetes Drug Treatment/Insulin/Lantus (Insulin Glargine [rDNA origin] Injection)/Lantus Warnings and Precautions

Lantus (Insulin Glargine) - Warnings and Precautions

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).

Page last updated: 2007-02-15

All Rights reserved - Copyright DrugLib.com, 2006-2009