Precedex® should be administered only by persons skilled in the management of patients in the intensive care setting. Due to the known pharmacological effects of Precedex®, patients should be continuously monitored while receiving Precedex®.

Clinically significant episodes of bradycardia and sinus arrest have been associated with Precedex® administration in young, healthy volunteers with high vagal tone or with different routes of administration including rapid intravenous or bolus administration.

General

Some patients receiving Precedex® have been observed to be arousable and alert when stimulated. This alone should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms.

Reports of hypotension and bradycardia have been associated with Precedex® infusion. If medical intervention is required, treatment may include decreasing or stopping the infusion of Precedex®, increasing the rate of IV fluid administration, elevation of the lower extremities, and use of pressor agents. Because Precedex® has the potential to augment bradycardia induced by vagal stimuli, clinicians should be prepared to intervene. The intravenous administration of anticholinergic agents (e.g., atropine) should be considered to modify vagal tone. In clinical trials, atropine or glycopyrrolate were effective in the treatment of most episodes of Precedex®-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required.

Caution should be exercised when administering Precedex® to patients with advanced heart block and/or severe ventricular dysfunction. Because Precedex® decreases sympathetic nervous system activity, hypotension and/or bradycardia may be expected to be more pronounced in hypovolemic patients and in those with diabetes mellitus or chronic hypertension and in the elderly.

In situations where other vasodilators or negative chronotropic agents are administered, coadministration of Precedex® could have an additive pharmacodynamic effect and should be administered with caution.

Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of Precedex®. Treatment of the transient hypertension has generally not been necessary, although reduction of the loading infusion rate may be desirable.

Precedex® infusion should not be co-administered through the same IV catheter with blood or plasma because physical compatibility has not been established. Safety and effectiveness of dexmedetomidine have not been evaluated in infusions over 24 hours. Dexmedetomidine is not indicated for infusions lasting over 24 hours (see INDICATIONS, DOSAGE AND ADMINISTRATION).

Withdrawal

Although not specifically studied, if Precedex® is administered chronically and stopped abruptly, withdrawal symptoms similar to those reported for another alpha-2-adrenergic agent, clonidine, may result. These symptoms include nervousness, agitation, and headaches, accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. Precedex® should not be administered for greater than 24 hours (see INDICATIONS, DOSAGE AND ADMINISTRATION).

Adrenal Insufficiency

Dexmedetomidine had no effect on ACTH-stimulated cortisol release in dogs after a single dose; however, after the subcutaneous infusion of dexmedetomidine for one week, the cortisol response to ACTH was diminished by approximately 40%.

Hepatic Impairment

Since dexmedetomidine clearance decreases with severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function (see CLINICAL PHARMACOLOGY, Pharmacokinetics, DOSAGE AND ADMINISTRATION).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal carcinogenicity studies have not been performed with dexmedetomidine.

Dexmedetomidine was not mutagenic in vitro, in either the bacterial reverse mutation assay (E. coli and Salmonella typhimurium) or the mammalian cell forward mutation assay (mouse lymphoma). Dexmedetomidine was clastogenic in the in vitro human lymphocyte chromosome aberration test with, but not without, metabolic activation. Dexmedetomidine was also clastogenic in the in vivo mouse micronucleus test.

Fertility in male or female rats was not affected after daily subcutaneous injections at doses up to 54 mcg/kg (less than the maximum recommended human intravenous dose on a mcg/m² basis). Dexmedetomidine was dosed from 10 weeks prior to mating in males and 3 weeks prior to mating and during mating in females.

Pregnancy: Teratogenic Effects. Pregnancy Category C

Teratogenic effects were not observed following administration of dexmedetomidine at subcutaneous doses up to 200 mcg/kg in rats from day 5 to day 16 of gestation and intravenous doses up to 96 mcg/kg in rabbits from day 6 to day 18 of gestation. The dose in rats is approximately 2 times the maximum recommended human intravenous dose on a mcg/m² basis. The exposure in rabbits is approximately equal to that in humans at the maximum recommended intravenous dose based on plasma area-under-the-curve values. However, fetal toxicity, as evidenced by increased postimplantation losses and reduced live pups, was observed in rats at subcutaneous dose of 200 mcg/kg. The no-effect dose was 20 mcg/kg (less than the maximum recommended human intravenous dose on a mcg/m² basis). In another reproductive study when dexmedetomidine was administered subcutaneously to pregnant rats from gestation day 16 through nursing, it caused lower pup weights at 8 and 32 mcg/kg as well as fetal and embryocidal toxicity of second generation offspring at a dose of 32 mcg/kg (less than the maximum recommended human intravenous dose on a mcg/m² basis). Dexmedetomidine also produced delayed motor development in pups at a dose of 32 mcg/kg (less than the maximum recommended human intravenous dose on a mcg/m² basis). No such effects were observed at a dose of 2 mcg/kg (less than the maximum recommended intravenous dose on a mcg/m² basis).

Placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously to pregnant rats.

There are no adequate and well-controlled studies in pregnant women. Dexmedetomidine should be used during pregnancy only if the potential benefits justify the potential risk to the fetus.

Labor and Delivery

The safety of Precedex® during labor and delivery has not been studied. Therefore, Precedex® is not recommended during labor and delivery including cesarean section deliveries.

Nursing Mothers

It is not known whether Precedex® is excreted in human milk. Radiolabeled dexmedetomidine administered subcutaneously to lactating female rats was excreted in milk. Because many drugs are excreted in human milk, caution should be exercised when Precedex® is administered to a nursing woman.

Pediatrics

There have been no clinical studies to establish the safety and efficacy of Precedex® in pediatric patients below 18 years of age. Therefore, Precedex® is not recommended for use in this population.

Geriatrics

A total of 531 subjects in the clinical studies were 65 years of age and over. A total of 129 subjects in the clinical studies were 75 years of age and over. In patients greater than 65 years of age, a higher incidence of bradycardia and hypotension was observed following administration of Precedex® (see PRECAUTIONS, General). Therefore a dose reduction may be considered in patients over 65 years of age.

Dexmedetomidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in elderly patients, and it may be useful to monitor renal function.

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