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Duraclon

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Duraclon

WARNINGS

Use in Postoperative or Obstetrical Analgesia

Duraclon (clonidine injection) (epidural clonidine) is not recommended for obstetrical, post-partum, or perioperative 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 (clonidine injection) 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 is usually responsive to intravenous fluids and, if necessary, appropriate parenterallyadministered 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 μg 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.

PRECAUTIONS

General

Cardiac Effects

Epidural clonidine frequently causes decreases in heart rate. Symptomatic bradycardia can be treated with atropine. Rarely, atrioventricular block greater than first degree has been reported. Clonidine does not alter the hemodynamic response to exercise, but may mask the increase in heart rate associated with hypovolemia.

Respiratory Depression and Sedation

Clonidine administration may result in sedation through the activation of alpha-adrenoceptors in the brainstem. High doses of clonidine cause sedation and ventilatory abnormalities that are usually mild. Tolerance to these effects can develop with chronic administration. These effects have been reported with bolus doses that are significantly larger than the infusion rate recommended for treating cancer pain.

Depression

Depression has been seen in a small percentage of patients treated with oral or transdermal clonidine. Depression commonly occurs in cancer patients and may be exacerbated by treatment with clonidine. Patients, especially those with a known history of affective disorders, should be monitored for the signs and symptoms of depression.

Pain of Visceral or Somatic Origin: In the clinical investigations, at doses tested, Duraclon (clonidine injection) was most effective in well-localized, “neuropathic” pain that was characterized as electrical, burning, or shooting in nature, and which was localized to a dermatomal or peripheral nerve distribution. Duraclon (clonidine injection) may be less effective, or possibly ineffective in the treatment of pain that is diffuse, poorly localized, or visceral in origin.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 132-week study in rats, clonidine hydrochloride administered as a dietary admixture at 5-8 times (based on body surface area) the 50 μg/kg maximum recommended daily human dose (MRDHD) for hypertension did not show any carcinogenic potential. Clonidine was inactive in the Ames test of mutagenicity. Fertility of male or female rats was unaffected by oral clonidine hydrochloride doses as high as 150 μg/kg, or about 0.5 times the MRDHD. Fertility of female rats did, however, appear to be affected in another experiment at oral dose levels of 500-2000 μg/kg, or 2-7 times the MRDHD.

Usage in Pregnancy/Teratogenic Effects

Pregnancy Category C: Reproduction studies in rabbits at clonidine hydrochloride doses up to approximately the MRDHD revealed no evidence of teratogenic or embryotoxic potential. In rats, however, doses as low as one-third the MRDHD were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating. Increased resorptions were not associated with treatment with the same or higher doses up to 0.5 times the MRDHD when dams were treated on days 6-15 of gestation. Increased resorptions were observed at higher levels (7times the MRDHD) in rats and mice treated on days 1-14 of gestation.

Clonidine readily crosses the placenta and its concentrations are equal in maternal and umbilical cord plasma; amniotic fluid concentrations can be 4-times those found in serum. There are no adequate and well-controlled studies in pregnant women during early gestation when organ formation takes place. Studies using epidural clonidine during labor have demonstrated no apparent adverse effects on the infant at the time of delivery. However, these studies did not monitor the infants for hemodynamic effects in the days following delivery. Clonidine hydrochloride injection should be used during pregnancy only if the potential benefits justify the potential risk to the fetus.

Labor and Delivery

There are no adequate controlled clinical trials evaluating the safety, efficacy, and dosing of Duraclon (clonidine injection) in obstetrical settings. Because maternal perfusion of the placenta is critically dependent on blood pressure, use of Duraclon (clonidine injection) as an analgesic during labor and delivery is not indicated (see WARNINGS).

Nursing Mothers

Concentrations of clonidine in human breast milk are approximately twice those found in maternal plasma. Caution should be exercised when clonidine is administered to a nursing woman. Because of the potential for severe adverse reactions in nursing infants, a decision should be made to either discontinue nursing or to discontinue clonidine.

Pediatric Use

The safety and effectiveness of Duraclon (clonidine injection) in this limited indication and clinical population have been established in patients old enough to tolerate placement and management of an epidural catheter, based on evidence from adequate and well controlled studies in adults and experience with the use of clonidine in the pediatric age group for other indications. The use of Duraclon (clonidine injection) should be restricted to pediatric patients with severe intractable pain from malignancy that is unresponsive to epidural or spinal opiates or other more conventional analgesic techniques. The starting dose of Duraclon (clonidine injection) should be selected on per kilogram basis (0.5 μg per kg per hour) and cautiously adjusted based on the clinical response.

Last reviewed on RxList: 8/18/2010
This monograph has been modified to include the generic and brand name in many instances.

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