CLONIDINE HCI

CLONIDINE HCI- clonidine hydrochloride injection, solution
HF Acquisition Co LLC, DBA HealthFirst

SPL UNCLASSIFIED

Rx Only

SPL1
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SPL2
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DESCRIPTION

Clonidine hydrochloride injection is a centrally-acting 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:

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

Each mL of the 1000 mcg/10 mL (0.1 mg/mL) concentration contains 100 mcg 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 1mg (1000 mcg) of clonidine hydrochloride.

Each mL of the 5000 mcg/10 mL (0.5 mg/mL) concentration contains 500 mcg 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 mcg) 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 mcg 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 mcg 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 mcg/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 14C-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 14C-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 uncharged 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 clonidine hydrochloride injection 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 was 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 & USAGE

Clonidine hydrochloride 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 PHARMACOLOGY: 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

Clonidine hydrochloride injection 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 clonidine hydrochloride injection 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

Clonidine hydrochloride injection (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 clonidine hydrochloride injection at 30 mcg/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, parenterally-administered pressor agents.

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.

Withdrawal

Sudden cessation of clonidine treatment, regardless of the route of administration, has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor, accompanied or followed by a rapid rise in blood pressure. The likelihood of such reactions appears to be greater after administration of higher doses or with concomitant beta-blocker treatment. Special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after abrupt clonidine withdrawal. Patients with a history of hypertension and/or other underlying cardiovascular conditions may be at particular risk of the consequences of abrupt discontinuation of clonidine. In the pivotal double-blind, randomized cancer pain study, four of 38 subjects receiving 720 mcg of clonidine per day experienced rebound hypertension following abrupt withdrawal. One of these patients with rebound hypertension subsequently experienced a cerebrovascular accident.

Careful monitoring of infusion pump function and inspection of catheter tubing for obstruction or dislodgement can help reduce the risk of inadvertent abrupt withdrawal of epidural clonidine. Patients should notify their physician immediately if clonidine administration is inadvertently interrupted for any reason. Patients should also be instructed not to discontinue therapy without consulting their physician.

When discontinuing therapy with epidural clonidine, the physician should reduce the dose gradually over 2 to 4 days to avoid withdrawal symptoms.

An excessive rise in blood pressure following discontinuation of epidural clonidine can be treated by administration of clonidine or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of epidural clonidine.

Infections

Infections related to implantable epidural catheters pose a serious risk. Evaluation of fever in a patient receiving epidural clonidine should include the possibility of a catheter-related infection such as meningitis or epidural abscess.

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