tic 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.

t be used with a preservative. parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. dosage

theter related infections occur in 5%-20% of patients, depending on the kind of catheter used, catheter placement technique, quality of the catheter care, and length of catheter placement. the inadvertent intrathecal administration of clonidine has not been associated with a significantly increased risk of adverse events, but there are inadequate safety and efficacy data to support the use of intrathecal clonidine. epidural clonidine was compared to placebo in a two week double-blind study of 85 terminal cancer patients with intractable pain receiving epidural morphine. the following adverse events were reported in two or more patients and may be related to administration of either clonidine hydrochloride injection or morphine. incidence of adverse events in the two-week trial an open label long-term extension of the above trial was performed. thirty-two subjects received epidural clonidine and morphine for up to 94 weeks with a median dosing period of 10 weeks. the following adverse events (and percent incidence) were reported: hypotension/postural hypotension (47%); nausea (13%); anxiety/confusion (38%); somnolence (25%); urinary tract infection (22%); constipation, dyspnea, fever, infection (6% each); asthenia, hyperaesthesia, pain, skin ulcer, and vomiting (5% each). eighteen percent of subjects discontinued this study as a result of catheter-related problems (infections, accidental dislodging, etc.), and one subject developed meningitis, possibly as a result of catheter-related infection. in this study, rebound hypertension was not assessed, and ecg and laboratory data not systematically sought. the following adverse reactions have also been reported with the use of any dosage form of clonidine. in many cases patients were receiving concomitant medication and a causal relationship has not been established: body as a whole: weakness, 10%; fatigue, 4%; headache and withdrawal syndrome, each 1%. also reported were pallor, a weakly positive coomb’s test, and increased sensitivity to alcohol. cardiovascular: palpitations and tachycardia, and bradycardia, each 0.5%. syncope, raynaud’s phenomenon, congestive heart failure, and electrocardiographic abnormalities (i.e., sinus node arrest, functional bradycardia, high degree av block) have been reported rarely. rare cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis. central nervous system: nervousness and agitation, 3%; mental depression, 1%; insomnia, 0.5%. cerebrovascular accidents, other behavioral changes, vivid dreams or nightmares, restlessness, and delirium have been reported rarely. dermatological: rash, 1%; pruritus, 0.7%; hives, angioneurotic edema and urticaria, 0.5%; alopecia, 0.2%. gastrointestinal: anorexia and malaise, each 1%; mild transient abnormalities in liver function tests, 1%; hepatitis, parotitis, ileus and pseudo obstruction, and abdominal pain, rarely. genitourinary: decreased sexual activity, impotence, and libido, 3%; nocturia, about 1%; difficulty in micturition, about 0.2%; urinary retention, about 0.1%. hematologic: thrombocytopenia, rarely. metabolic: weight gain, 0.1%; gynecomastia, 1%; transient elevation of glucose or serum phosphatase, rarely. musculoskeletal: muscle or joint pain, about 0.6%; leg cramps, 0.3%. oro-otolaryngeal: dryness of the nasal mucosa was rarely reported. ophthalmological: dryness of the eyes, burning of the eyes and blurred vision were rarely reported. to report suspected adverse reactions, contact west-ward pharmaceutical corp. at 1-877-233-2001, or the fda at 1-800-fda-1088 or www.fda.gov/medwatch. adverse

± 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.