Duraclon

DURACLON- clonidine hydrochloride injection, solution
Xanodyne Pharmaceuticals, Inc.

Rx only

The 500μ g/mL strength product should be diluted prior to use in an appropriate solution.

NOTE: Duraclon ® (epidural clonidine) is not recommended for obstetrical, postpartum, or peri-operative pain management. The risk of hemodynamic instability, especially hypotension and bradycardia, from epidural clonidine may be unacceptable in these patients. However, in a rare obstetrical, post-partum or peri-operative patient, potential benefits may outweigh the possible risks.

DESCRIPTION:

Duraclon (clonidine hydrochloride injection) is a centrally-acting analgesic solution for use in continuous epidural infusion devices.

Clonidine Hydrochloride, USP, is an imidazoline derivative and exists as a mesomeric compound. The chemical names are Benzenamine,2,6-dichloro-N-2-imidazolidinylidene monohydrochloride and 2-[(2,6-dichlorophenyl) imino]imidazolidine monohydrochloride. The following is the structural formula:

Clonidine Hydrochloride Structural Formula
(click image for full-size original)

Duraclon (clonidine hydrochloride injection) is supplied as a clear, colorless, preservative-free, pyrogen-free, aqueous sterile solution (pH 5 to 7) in single-dose, 10 mL vials.

Each mL of the 100 μ g/mL (0.1 mg/mL) concentration contains 100 μ g of Clonidine Hydrochloride, USP and 9 mg Sodium Chloride, USP in Water for Injection, USP. Hydrochloric Acid and/or Sodium Hydroxide may have been added for pH adjustment. Each 10 mL vial contains 1 mg (1000 μ g) of clonidine hydrochloride.

Each mL of the 500 μ g/mL (0.5 mg/mL) concentration contains 500 μ g of Clonidine Hydrochloride, USP and 9 mg Sodium Chloride, USP in Water for Injection, USP. Hydrochloric Acid and/or Sodium Hydroxide may have been added for pH adjustment. Each 10 mL vial contains 5 mg (5000 μ g) of clonidine hydrochloride.

CLINICAL PHARMACOLOGY:

Mechanism of Action

Epidurally administered clonidine produces dose-dependent analgesia not antagonized by opiate antagonists. The analgesia is limited to the body regions innervated by the spinal segments where analgesic concentrations of clonidine are present. Clonidine is thought to produce analgesia at presynaptic and postjunctional alpha-2-adrenoceptors in the spinal cord by preventing pain signal transmission to the brain.

Pharmacokinetics

Following a 10 minute intravenous infusion of 300 μ g clonidine HCl to five male volunteers, plasma clonidine levels showed an initial rapid distribution phase (mean±SD t1/2 =11±9 minutes) followed by a slower elimination phase (t1/2 =9±2 hours) over 24 hours. Clonidine’s total body clearance (CL) was 219±92 mL/min.

Following a 700 μ g clonidine HCl epidural dose given over five minutes to four male and five female volunteers, peak clonidine plasma levels (4.4±1.4 ng/mL) were obtained in 19±27 minutes. The plasma elimination half-life was determined to be 22±15 hours following sample collection for 24 hours. CL was 190±70 mL/min. In cerebral spinal fluid (CSF), peak clonidine levels (418±255 ng/mL) were achieved in 26±11 minutes. The clonidine CSF elimination half-life was 1.3±0.5 hours when samples were collected for 6 hours. Compared to men, women had a lower mean plasma clearance, longer mean plasma half-life, and higher mean peak level of clonidine in both plasma and CSF.

In cancer patients who received 14 days of clonidine HCl epidural infusion (rate=30 μ g/hr) plus morphine by patient-controlled analgesia (PCA), steady state clonidine plasma concentrations of 2.2±1.1 and 2.4±1.4 ng/mL were obtained on dosing days 7 and 14, respectively. CL was 279±184 and 272±163 mL/min on these days. CSF concentrations were not determined in these patients.

Distribution

Clonidine is highly lipid soluble and readily distributes into extravascular sites including the central nervous system. Clonidine’s volume of distribution is 2.1±0.4 L/kg. The binding of clonidine to plasma protein is primarily to albumin and varies between 20 and 40% in vitro. Epidurally administered clonidine readily partitions into plasma via the epidural veins and attains systemic concentrations (0.5 — 2.0 ng/mL) that are associated with a hypotensive effect mediated by the central nervous system.

Excretion

Following an intravenous dose of 14 C-clonidine, 72% of the administered dose was excreted in urine in 96 hours of which 40-50% was unchanged clonidine. Renal clearance for clonidine was determined to be 133±66 mL/min. In a study where 14 C-clonidine was given to subjects with varying degrees of kidney function, elimination half-lives varied (17.5 to 41 hours) as a function of creatinine clearance. In subjects undergoing hemodialysis only 5% of body clonidine stores were removed.

Metabolism

In humans, clonidine metabolism follows minor pathways with the major metabolite, p-hydroxy-clonidine, being present at less than 10% of the concentration of unchanged drug in urine.

Special Populations

The pharmacokinetics of epidurally administered clonidine has not been studied in the pediatric population or in patients with renal or hepatic disease.

Clinical Trials

In a double-blind, randomized study of cancer patients with severe intractable pain below the C4 dermatome not controlled by morphine, 38 patients were randomized to an epidural infusion of Duraclon plus epidural morphine, whereas 47 subjects received epidural placebo plus epidural morphine. Both groups were allowed rescue doses of epidural morphine. Successful analgesia, defined as a decrease in either morphine use or Visual Analog Score (VAS) pain, was significantly more common with epidural clonidine than placebo (45% vs 21%, p=0.016). Only the subgroup of 36 patients with “neuropathic” pain, characterized by the investigator as well-localized, burning, shooting, or electric-like pain in a dermatomal or peripheral nerve distribution had significant analgesic effects relative to placebo in this study.

The most frequent adverse events with clonidine were hypotension (45% vs 11% for placebo, p< 0.001), postural hypotension (32% vs 0%, p< 0.001), dizziness (13% vs 4%, p=0.234), anxiety (11% vs 2%, p=0.168) and dry mouth (13% vs 9%, p=0.505). Both mean blood pressure and heart rate were reduced in the clonidine group. At the conclusion of the two week study period in the clinical trial, all patients were abruptly withdrawn from study drug or placebo. Four patients of the clonidine group suffered rebound hypertension upon withdrawal of clonidine; one of these patients suffered a cerebrovascular accident. Asymptomatic bradycardia was noted in one clonidine patient.

INDICATIONS AND USAGE:

Duraclon is indicated in combination with opiates for the treatment of severe pain in cancer patients that is not adequately relieved by opioid analgesics alone. Epidural clonidine is more likely to be effective in patients with neuropathic pain than somatic or visceral pain (see Clinical Trials).

The safety of this drug product has only been established in a highly selected group of cancer patients, and only after an adequate trial of opioid analgesia. Other use is of unproven safety and is not recommended. In a rare patient, the potential benefits may outweigh the known risks (see WARNINGS).

CONTRAINDICATIONS:

Duraclon is contraindicated in patients with a history of sensitization or allergic reactions to clonidine. Epidural administration is contraindicated in the presence of an injection site infection, in patients on anticoagulant therapy, and in those with a bleeding diathesis. Administration of Duraclon above the C4 dermatome is contraindicated since there are no adequate safety data to support such use. (see WARNINGS).

WARNINGS:

Use in Postoperative or Obstetrical Analgesia

Duraclon (epidural clonidine) is not recommended for obstetrical, post-partum, or peri-operative pain management. The risk of hemodynamic instability, especially hypotension and bradycardia, from epidural clonidine may be unacceptable in these patients.

Hypotension

Because severe hypotension may follow the administration of clonidine, it should be used with caution in all patients. It is not recommended in most patients with severe cardiovascular disease or in those who are otherwise hemodynamically unstable. The benefit of its administration in these patients should be carefully balanced against the potential risks resulting from hypotension.

Vital signs should be monitored frequently, especially during the first few days of epidural clonidine therapy. When clonidine is infused into the upper thoracic spinal segments, more pronounced decreases in the blood pressure may be seen.

Clonidine decreases sympathetic outflow from the central nervous system resulting in decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. However, in the absence of profound hypotension, renal blood flow and glomerular filtration rate remain essentially unchanged.

In the pivotal double-blind, randomized study of cancer patients, where 38 subjects were administered epidural Duraclon at 30 μg/hr in addition to epidural morphine, hypotension occurred in 45% of subjects. Most episodes of hypotension occurred within the first four days after beginning epidural clonidine. However, hypotensive episodes occurred throughout the duration of the trial. There was a tendency for these episodes to occur more commonly in women, and in those with higher serum clonidine levels. Patients experiencing hypotension also tended to weigh less than those who did not experience hypotension. The hypotension usually responded to intravenous fluids and, if necessary, parenteral ephedrine.

Published reports on the use of epidural clonidine for intraoperative or postoperative analgesia also show a consistent and marked hypotensive response to clonidine. Severe hypotension may occur even if intravenous fluid pretreatment is given.

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