Categories: Hypertension; Pregnancy Category C; FDA Approved 1984 Oct; Orphan Drugs
FDA Drug Class: Antihypertensives
Brand Names: Arkamin; Barclyd; Capril; Caprysin;
Catapres; Catapres-TTS; Catapres TTS; Catapresan;
Catapresan 100; Catapresan Depot; Catapresan TTS;
Catapressan; Clonidine; Daipres; Dixarit; Haemiton;
Normopresan; Paracefan; Sulmidine; Taitecin
(Foreign brand names outside U.S. in italics)
Boxed Warning
Description
Clinical Pharmacology
Clinical Studies
Indications and Usage
Contraindications
Warnings
Precautions
Drug Interactions
Adverse Reactions
Overdosage
Dosage and Administration
How Supplied
| Note: Epidural clonidine is not recommended for obsetrical, 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. However, in a rare obstetrical, post-partum or peri-operative patient, potential benefits may outweigh the possible risks. |
Clonidine hydrochloride USP is a centrally acting antihypertensive agent available as tablets for oral administration in three dosage strengths: 0.1 mg, 0.2 mg and 0.3 mg. The 0.1 mg tablet is equivalent to 0.087 mg of the free base.
The inactive ingredients in Catapres are colloidal silicon dioxide, corn starch, dibasic calcium phosphate, FD&C Yellow No. 6, gelatin, glycerin, lactose, magnesium stearate, methylparaben, propylparaben. The Catapres 0.1 mg tablet also contains FD&C Blue No. 1 and FD&C Red No. 3.
Clonidine hydrochloride is an imidazoline derivative and exists as a mesomeric compound. The chemical name is 2-(2,6-dichlorophenylamino)-2- imidazoline hydrochloride. It has the following molecular formula: C9H9CI2N3 · HCl, with molecular weight of 266.56.
Clonidine hydrochloride is an odorless, bitter, white, crystalline substance soluble in water and alcohol.
Clonidine hydrochloride injection is a centrally-acting analgesic solution for use in continuous epidural infusion devices.
Clonidine hydrochloride 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. Its molecular formula is C9H9CI2N3 · HCl, with molecular weight of 266.56.
Clonidine hydrochloride injection is supplied as a clear, colorless, preservative-free, pyrogen-free, aqueous sterile solution (pH 5 to 7) in a single-dose, 10 ml vial. Each ml of solution 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 1 mg (1000 mcg) of clonidine hydrochloride.
Clonidine hydrochloride acts relatively rapidly. The patient's blood pressure declines within 30 to 60 minutes after an oral dose, the maximum decrease occurring within 2 to 4 hours. The plasma level of clonidine hydrochloride peaks in approximately 3 to 5 hours and the plasma half-life ranges from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function. Following oral administration about 40-60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. About 50% of the absorbed dose is metabolized in the liver.
Clonidine stimulates alpha-adrenoreceptors in the brain stem, resulting in reduced sympathetic outflow from the central nervous system and a decrease in peripheral resistance: at a 45° tilt there is a smaller reduction in cardiac output and a decrease of peripheral resistance. During long-term therapy, cardiac output tends to return to control values, while peripheral resistance remains decreased. Slowing of the pulse rate has been observed in most patients given clonidine, but the drug does not alter normal hemodynamic response to exercise.
Other studies in patients have provided evidence of a reduction in plasma renin activity and in the excretion of aldosterone and catecholamines, but the exact relationship of these pharmacologic actions to the antihypertensive effect has not been fully elucidated.
Clonidine acutely stimulates growth hormone release in both children and adults, but does not produce a chronic elevation of growth hormone with long-term use.
Tolerance may develop in some patients, necessitating a reevaluation of therapy.
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 t½ = 11±9 minutes) followed by a slower elimination phase (t½ = 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 was removed.
Metabolism: In humans, clonidine metabolism follows minor pathways with the major metabolite, p-hydroxyclonidine, 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.
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 HCl 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 withdrawl of clonidine; one of these patients suffered a cerebrovascular accident. Asymptomatic bradycardia was noted in one clonidine patient.
Clonidine hydrochloride is indicated in the treatment of hypertension. Clonidine hydrochloride may be employed alone or concomitantly with other antihypertensive agents.
Epidural clonidine HCl 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 STUDIES.)
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.)
None known.
Clonidine HCl 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 epidural clonidine HCl above the C4 dermatome is contraindicated since there are no adequate data to support such use (see WARNINGS.)
Use in Postoperative or Obstetrical Analgesia: 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 HCl at 30 mcg/hr in addition to epidural morphine, hypertension occurred in 45% of subjects. Most episodes of hypotension occurred within the first fours 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, parenteral ephedrine.
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 if intravenous fluid pretreatment is given.
Withdrawl: 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 withdrawl. Patients with a history of hypertension and/or other underlying cardiovascular conditions may be at 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 withdrawl. 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 withdrawl 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 withdrawl 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 catheter-related infection such as meningitis or epidural abscess.
General: In patients who have developed localized contact sensitization to clonidine film, substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash.
In patients who develop an allergic reaction from clonidine film that extends beyond the local patch site (such as generalized skin rash, urticaria, or angioedema), oral clonidine hydrochloride substitution may elicit a similar reaction.
As with all antihypertensive therapy, clonidine hydrochloride should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease or chronic renal failure.
Withdrawal: Patients should be instructed not to discontinue therapy without consulting their physician. Sudden cessation of clonidine treatment has resulted in subjective symptoms such as nervousness, agitation and headache, accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma, but such occurrences have usually been associated with previous administration of high oral doses (exceeding 1.2 mg/day) and/or with continuation of concomitant beta-blocker therapy. Rare instances of hypertensive encephalopathy and death have been reported. When discontinuing therapy with clonidine hydrochloride, the physician should reduce the dose gradually over 2 to 4 days withdrawal symptomatology.
An excessive rise in blood pressure following clonidine hydrochloride discontinuance can be reversed by administration of oral clonidine or by intravenous phentolamine. If therapy is to be discontinued in patients receiving beta-blockers and clonidine concurrently, beta-blockers should be discontinued several days before the gradual withdrawal of clonidine hydrochloride.
Perioperative Use: Administration of clonidine hydrochloride should be continued to within four hours of surgery and resumed as soon as possible thereafter. The blood pressure should be carefully monitored and appropriate measures instituted to control it as necessary.
Information for Patients: Patients who engage in potentially hazardous activities, such as operating machinery or driving, should be advised of a potential sedative effect of clonidine. Patients should be cautioned against interruption of clonidine hydrochloride therapy without a physician's advice.
Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 132-week (fixed concentration) dietary administration study in rats, clonidine hydrochloride administered at 32 to 46 times the maximum recommended daily human dose was unassociated with evidence of carcinogenic potential.
Fertility of male or female rats was unaffected by clonidine hydrochloride doses as high as 150 mcg/kg or about 3 times the maximum recommended daily human dose (MRDHD). Fertility of female rats did, however, appear to be affected (in another experiment) at dose levels of 500 to 2000 mcg/kg or 10 to 40 times the MRDHD.
Usage in Pregnancy: Teratogenic Effects: Pregnancy Category C: Reproduction studies performed in rabbits at doses up to approximately 3 times the maximum recommended daily human dose (MRDHD) of clonidine hydrochloride have revealed no evidence of teratogenic or embryotoxic potential in rabbits. In rats, however, doses as low as 1/3 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 at the same or at higher dose levels (up to 3 times the MRDHD) when dams were treated days 6-15 of gestation. Increased resorptions were observed at much higher levels (40 times the MRDHD) in rats and mice treated days 1-14 of gestation (lowest dose employed in that study was 500 mcg/kg). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers: As clonidine hydrochloride is excreted in human milk, caution should be exercised when clonidine hydrochloride is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in children have not been established.
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, epidural clonidine HCl 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. Epidural clonidine HCl may be less effective, or possibly ineffective in the treatment of pain that is diffuse, poorly localized, or visceral in origin.
Patients should be instructed about the risks of rebound hypertension and warned not to discontinue clonidine except under the supervision of a physician. Patients should notify their physician immediately if clonidine administration is inadvertently interrupted for any reason. Patients who engage in potentially hazardous activities, such as operating machinery or driving, should be advised of the potential sedative and hypotensive effects of epidural clonidine. They should also be informed that sedative effects may be increased by CNS-depressing drugs such as alcohol and barbiturates, and that hypotensive effects may be increased by opiates.
In a 132-week study in rats, clonidine HCl administered as a dietary admixture at 5-8 times (based on body surface area) the 50 mcg/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 and female rats was unaffected by oral clonidine HCl doses as high as 150 mcg/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 mcg/kg, or 2-7 times the MRDHD.
Reproduction studies in rabbits at clonidine HCl 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 (7-times 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 HCl injection should be used during pregnancy only if the potential benefits justify the potential risk to the fetus.
There are no adequate controlled clinical trials evaluating the safety, efficacy, and dosing of epidural clonidine HCl in obstetrical settings. Because maternal perfusion of the placenta is critically dependent on blood pressure, use of epidural clonidine HCl as an analgesic during labor and delivery is not indicated (see WARNINGS.)
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.
The safety and effectiveness of epidural clonidine HCl 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 epidural clonidine HCl 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 epidural clonidine HCl should be selected on per kilogram basis (0.5 mcg per kg per hour) and cautiously adjusted based on the clinical response.
If a patient receiving clonidine hydrochloride is also taking tricyclic antidepressants, the effect of clonidine may be reduced, thus necessitating an increase in dosage. Clonidine hydrochloride may enhance the CNS-depressive effects of alcohol, barbiturates or other sedatives. Amitriptyline in combination with clonidine enhances the manifestation of corneal lesions in rats (See DOSAGE AND ADMINISTRATION, Toxicology.)
Clonidine may potentiate the CNS-depressive effect of alcohol, barbiturates or other sedating drugs. Narcotic analgesics may potentiate the hypotensive effects of clonidine. Tricyclic antidepressants may antagonize the hypotensive effects of clonidine. The effects of tricyclic antidepressants on clonidine's analgesic actions are not known.
Beta blockers may exacerbate the hypertensive response seen with clonidine withdrawl. Also, due to the potential for additive effects such as bradycardia and AV block, caution is warranted in patients receiving clonidine with agents known to affect sinus node function or AV nodal conduction (e.g., digitalis, calcium channel blockers, and beta-blockers.)
There is one reported case of a patient with acute delirium associated with the simultaneous use of fluphenazine and oral clonidine. Symptoms resolved when clonidine was withdrawn and recurred when the patient was rechallenged with clonidine.
Epidural clonidine may prolong the duration of pharmacologic effects of epidural local anesthetics, including both sensory and motor blockade.
Most adverse effects are mild and tend to diminish with continued therapy. The most frequent (which appear to be dose-related) are dry mouth, occurring in about 40 to 100 patients; drowsiness, about 33 in 100; dizziness, about 16 in 100; constipation and sedation, each about 10 in 100.
The following less frequent adverse experiences have also been reported in patients receiving clonidine hydrochloride, but in many cases patients were receiving concomitant medication and a causal relationship has not been established.
Gastrointestinal: Nausea and vomiting, about 5 in 100 patients; anorexia and malaise, each about 1 in 100; mild transient abnormalities in liver function tests, about 1 in 100; rare reports of hepatitis; parotitis, rarely.
Metabolic: Weight gain, about 1 in 100 patients; gynecomastia, about 1 in 1000; transient elevation of blood glucose or serum creatine phosphokinase, rarely.
Central Nervous System: Nervousness and agitation, about 3 in 100 patients; mental depression, about 1 in 100; headache, about 1 in 100; insomnia, about 5 in 1000. Vivid dreams or nightmares, other behavioral changes, restlessness, anxiety, visual and auditory hallucinations and delirium have been reported.
Cardiovascular: Orthostatic symptoms, about 3 in 100 patients; palpitations and tachycardia, and bradycardia, each about 5 in 1000. Raynaud's phenomenon, congestive heart failure, and electrocardiographic abnormalities i.e., conduction disturbances and arrhythmias have been reported rarely. Rare cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis.
Dermatological: Rash, about 1 in 100 patients; pruritus, about 7 in 1000; hives, angioneurotic edema and urticaria, about 5 in 1000; alopecia, about 2 in 1000.
Genitourinary: Decreased sexual activity, impotence and loss of libido, about 3 in 100 patients; nocturia, about 1 in 100; difficulty in micturition, about 2 in 1000; urinary retention, about 1 in 1000.
Other: Weakness, about 10 in 100 patients; fatigue, about 4 in 100; discontinuation syndrome, about 1 in 100; muscle or joint pain, about 6 in 1000 and cramps of the lower limbs, about 3 in 1000. Dryness, burning of the eyes, blurred vision, dryness of the nasal mucosa, pallor, weakly positive Coombs' test, increased sensitivity to alcohol and fever have been reported.
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, parenterally-administered ephedrine. 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 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 adverse events in TABLE 1 were reported in two or more patients and may be related to administration of either epidural clonidine HCl or morphine.
Hematologic: Theombocytopenia, 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.
The signs and symptoms of clonidine hydrochloride overdosage include hypotension, bradycardia, lethargy, irritability, weakness, somnolence, diminished or absent reflexes, miosis, vomiting and hypoventilation. With large overdoses, reversible cardiac conduction defects or arrhythmias, apnea, seizures and transient hypertension have been reported. The oral LD50of clonidine in rats was 465 mg/kg, and in mice 206 mg/kg.
The general treatment of clonidine hydrochloride overdosage may include intravenous fluids as indicated. Bradycardia can be treated with intravenous fluids as indicated. Bradycardia can be treated with intravenous atropine sulfate and hypotension with dopamine infusion in addition to intravenous fluids. Hypertension, associated with overdosage, has been treated with intravenous furosemide or diazoxide or alpha-blocking agents such as phentolamine. Tolazoline, an alpha-blocker, in intravenous doses of 10 mg at 30-minute intervals, may reverse clonidine's effects if other efforts fail. Routine hemodialysis is of limited benefit, since a maximum of 5% of circulating clonidine is removed.
In a patient who ingested 100 mg clonidine hydrochloride, plasma clonidine levels were 60 ng/ml (one hour), 190 ng/ml (1.5 hours), 370 ng/ml (two hours) and 120 ng/ml (5.5 and 6.5 hours). This patient developed hypertension followed by hypotension, bradycardia, apnea, hallucinations, semicoma, and premature ventricular contractions. The patient fully recovered after intensive treatment.
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 useful adjunct in the treatment of clonidine-induced respiratory depression, hypotension, and/or coma; blood pressure should be monitored since 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 HCl powder. This patient developed hypertension followed by hypotension, bradycardia, apnea, hallucinations, semicoma, 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.
Adults: The dose of clonidine hydrochloride must be adjusted according to the patient's individual blood pressure response. The following is a general guide to its administration.
Initial Dose: 0.1 mg tablet twice daily (morning and bedtime). Elderly patients may benefit from a lower initial dose.
Maintenance Dose: Further increments of 0.1 mg per day may be made if necessary until the desired response is achieved. Taking the larger portion of the oral daily dose at bedtime may minimize transient adjustment effects of dry mouth and drowsiness. The therapeutic doses most commonly employed have ranged from 0.2 mg to 0.6 mg per day given in divided doses. Studies have indicated that 2.4 mg is the maximum effective daily dose, but doses as high as this have rarely been employed.
Renal Impairment: Dosage must be adjusted according to the degree of 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.
Toxicology: In several studies, oral clonidine hydrochloride produced a dose-dependent increase in the incidence and severity of spontaneously occurring retinal degeneration in albino rats treated for six months or longer. Tissue distribution studies in dogs and monkeys revealed that clonidine hydrochloride was concentrated in the choroid of the eye. In view of the retinal degeneration observed in rats, eye examinations were performed in 908 patients prior to the start of clonidine hydrochloride therapy, who were then examined periodically thereafter. In 353 of these 908 patients, examinations were performed for periods of 24 months or longer. Except for some dryness of the eyes, no drug-related abnormal ophthalmologic findings were recorded and clonidine hydrochloride did not alter retinal function as shown by specialized tests such as the electroretinogram and macular dazzle. In rats, clonidine hydrochloride in combination with amitriptyline produced corneal lesions within 5 days.
The recommended starting dose of epidural clonidine HCl 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.
Dosage for Impaired Renal Function: 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.
Epidural clonidine HCl must not be used with a preservative.
Store below 86°F (30°).
Dispense in tight, light-resistant container.
Store at controlled room temperature 15°-30°C (59°-86°F). Preservative Free. Discard unused portion.
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