Clonidine Injection

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 to 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 to 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 was 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 clonidine hydrochloride 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.

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 (seeCLINICAL 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 (seeWARNINGS).

Hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, irritability, and miosis. With large oral overdoses, reversible cardiac conduction defects or arrhythmias, apnea, coma, and seizures have been reported. As little as 100 mcg of oral clonidine has produced signs of toxicity in pediatric patients.

There is no specific antidote for clonidine overdosage. Supportive care may include atropine sulfate for bradycardia, intravenous fluids and/or vasopressor agents for hypotension. Hypertension associated with overdosage has been treated with intravenous furosemide, diazoxide or alpha-blocking agents such as phentolamine. Naloxone may be a useful adjunct in the treatment of clonidine-induced respiratory depression, hypotension, and/or coma; blood pressure should be monitored since the administration of naloxone has occasionally resulted in paradoxical hypertension. Tolazoline administration has yielded inconsistent results and is not recommended as first-line therapy. Dialysis is not likely to significantly enhance the elimination of clonidine.

The largest overdose reported to date involved a 28-year old white male who ingested 100 mg of clonidine hydrochloride powder. This patient developed hypertension followed by hypotension, bradycardia, apnea, hallucinations, semi-coma, and premature ventricular contractions. The patient fully recovered after intensive treatment. Plasma clonidine levels were 60 ng/mL after 1 hour, 190 ng/mL after 1.5 hours, 370 ng/mL after 2 hours, and 120 ng/mL after 5.5 and 6.5 hours. In mice and rats, the oral LD50 of clonidine is 206 and 465 mg/kg, respectively.

The recommended starting dose of clonidine hydrochloride for continuous epidural infusion is 30 mcg/hr. Although dosage may be titrated up or down depending on pain relief and occurrence of adverse events, experience with dosage rates above 40 mcg/hr is limited.

Familiarization with the continuous epidural infusion device is essential. Patients receiving epidural clonidine from a continuous infusion device should be closely monitored for the first few days to assess their response.

The 500 mcg/mL (0.5 mg/mL) strength product must be diluted prior to use in 0.9% Sodium Chloride for Injection, U.S.P., to a final concentration of 100 mcg/mL:

Renal Impairment:Dosage should be adjusted according to the degree of renal impairment, and patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis.

Clonidine hydrochloride mustnotbe used with a preservative.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Clonidine hydrochloride injection is available as:

100 mcg/mL solution in 10 mL vials, packaged individually – NDC 0517-0730-01

500 mcg/mL solution in 10 mL vials, packaged individually – NDC 0517-0731-01

Store at 20°to 25°C (68°to 77°F); excursions permitted to 15°to 30°C (59°to 86°F) (See USP Controlled Room Temperature).

Preservative Free. Discard unused portion.

AMERICAN
REGENT, INC.
SHIRLEY, NY 11967

RQ1062-00
Revised: July 2016

PRINCIPAL DISPLAY PANEL - 10 mL (1,000 mcg) Label

NDC 0517-0730-01

CLONIDINE
HYDROCHLORIDE
INJECTION
1000 mcg/10 mL
(100 mcg/mL)

10 mLSINGLE DOSE VIAL

FOR EPIDURAL INJECTION

Rx Only

AMERICAN
REGENT, INC.
SHIRLEY, NY 11967

PRINCIPAL DISPLAY PANEL - 10 mL (5,000 mcg) Label

NDC 0517-0731-01

CLONIDINE
HYDROCHLORIDE
INJECTION

5000 mcg/10 mL
(500 mcg/mL)

10 mLSINGLE DOSE VIAL

FOR EPIDURAL INJECTION

MUST BE DILUTED BEFORE USE

Rx Only

AMERICAN
REGENT, INC.
SHIRLEY, NY 11967

PRINCIPAL DISPLAY PANEL - 10 mL (1,000 mcg) Carton

NDC 0517-0730-01

CLONIDINE
HYDROCHLORIDE
INJECTION

1000 mcg/10 mL
(100 mcg/mL)

FOR EPIDURAL INJECTION

10 mLSINGLE DOSE VIAL

Rx Only

AMERICAN
REGENT, INC.
SHIRLEY, NY 11967

PRINCIPAL DISPLAY PANEL - 10 mL (5,000 mcg) Carton

NDC 0517-0731-01

CLONIDINE
HYDROCHLORIDE
INJECTION

5000 mcg/10 mL
(500 mcg/mL)

10 mLSINGLE DOSE VIAL

FOR EPIDURAL INJECTION

MUST BE DILUTED BEFORE USE

Rx Only

AMERICAN
REGENT, INC.
SHIRLEY, NY 11967