|Labeler Name||West-ward Pharmaceutical Corp|
|Dosage & Substance||injection, solution clonidine hydrochloride|
|Date First Marketed||January 01, 2011|
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).
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).
Adverse reactions seen during continuous epidural clonidine infusion are dose-dependent and typical for a compound of this pharmacologic class. The adverse events most frequently reported in the pivotal controlled clinical trial of continuous epidural clonidine administration consisted of hypotension, postural hypotension, decreased heart rate, rebound hypertension, dry mouth, nausea, confusion, dizziness, somnolence, and fever. Hypotension is the adverse event that most frequently requires treatment. The hypotension is usually responsive to intravenous fluids and, if necessary, appropriate parenterally-administered pressor agents. Hypotension was observed more frequently in women and in lower weight patients, but no dose-related response was established.
Implantable epidural catheters are associated with a risk of catheter-related infections, including meningitis and/or epidural abscess. The risk depends on the clinical situation and the type of catheter used, but catheter 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.
|Adverse Events|| Clonidine |
N = 38
| Placebo |
N = 47
|Total Number of Patients Who Experienced at Least One Adverse Events||37 (97.4)||38 (80.5)|
|Hypotension||17 (44.8)||5 (10.6)|
|Postural Hypotension||12 (31.6)||0 (0)|
|Dry Mouth||5 (13.2)||4 ( 8.5)|
|Nausea||5 (13.2)||10 (21.3)|
|Somnolence||5 (13.2)||10 (21.3)|
|Dizziness||5 (13.2)||2 (4.3)|
|Confusion||5 (13.2)||5 (10.6)|
|Vomiting||4 (10.5)||7 (14.9)|
|Nausea/Vomiting||3 (7.9)||1 (2.1)|
|Sweating||2 (5.3)||0 (0)|
|Chest Pain||2 (5.3)||0 (0)|
|Hallucination||2 (5.3)||1 (2.1)|
|Tinnitus||2 (5.3)||0 (0)|
|Constipation||1 (2.6)||2 (4.3)|
|Tachycardia||1 (2.6)||2 (4.3)|
|Hypoventilation||1 (2.6)||2 (4.3)|
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.
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.
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.
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 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.
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.
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, clonidine hydrochloride 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. Clonidine hydrochloride injection may be less effective, or possibly ineffective in the treatment of pain that is diffuse, poorly localized, or visceral in origin.
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:
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.