000846 Clonidine Hydrochloride

COST OF THERAPY: 41.42 (Hypertension; Catapres; 0.1 mg; 2 tablets/day/day; 30 days)

COST OF THERAPY: 39.68 (Hypertension; Catapres-TTS; 0.1 mg; 1 patch/week/day; 30 days)

HCFA JCODE(S): J0735; 1 mg; epidural

BOXED WARNING

The 500 μg/ml strength product should be diluted prior to use in an appropriate solution.

Note:

DESCRIPTION

Clonidine HCl injection is a centrally-acting analgesic solution for use in continuous epidural infusion devices.

Clonidine HCl 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 C9H9Cl2N3.HCl, with molecular weight of 266.56.

Clonidine HCl injection is supplied as a clear, colorless, preservative-free, pyrogen-free, aqueous sterile solution (pH 5-7) in a single-dose, 10 ml vial.

100 μg/ml:

500 μg/ml:

CLINICAL PHARMACOLOGY

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 μg clonidine HCl to 5 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 μg clonidine HCl epidural dose given over 5 minutes to 4 male and 5 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 μg/h) 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.

CLINICAL STUDIES

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 2 week study period in the clinical trial, all patients were abruptly withdrawn from study drug or placebo. Four (4) patients of the clonidine group suffered rebound hypertension upon withdrawl of clonidine; 1 of these patients suffered a cerebrovascular accident. Asymptomatic bradycardia was noted in 1 clonidine patient.

INDICATIONS AND USAGE

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).

CONTRAINDICATIONS

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 safety data to support such use (see WARNINGS).

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 μg/h in addition to epidural morphine, hypertension occurred in 45% of subjects. Most episodes of hypotension occurred within the first 4 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.

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 withdrawl. 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, 4 of 38 subjects receiving 720 μg 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 2-4 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.

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, 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.

Information for the Patient

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.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

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 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 and female rats was unaffected by oral clonidine HCl 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.

Pregnancy, Teratogenic Effects, Pregnancy Category C

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.

Labor and Delivery

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).

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 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 μg/kg/h) and cautiously adjusted based on the clinical response.

DRUG INTERACTIONS

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 withdrawal. 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.

ADVERSE REACTIONS

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 2 week double-blind study of 85 terminal cancer patients with intractable pain receiving epidural morphine. The adverse events in TABLE 1 were reported in 2 or more patients and may be related to administration of either epidural clonidine HCl or morphine.

An open label long-term extension of the trial was performed. Thirty-two (32) 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 (18%) 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 a catheter-related infection. In this study, rebound hypertension was not assessed, and ECG and laboratory data were not systemically 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:

Cardiovascular:

Central Nervous System:

Dermatological:

Gastrointestinal:

Genitourinary:

Hematologic:

Metabolic:

Musculoskeletal:

Oro-Otolaryngeal:

Ophthalmological:

OVERDOSAGE

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 μg 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.

DOSAGE AND ADMINISTRATION

The recommended starting dose of epidural clonidine HCl for continuous epidural infusion is 30 μg/h. Although dosage may be titrated up or down depending on pain relief and occurrence of adverse events, experience with dosage rates above 40 μg/h 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 μg/ml (0.5 mg/ml) strength product must be diluted prior to use in 0.9% sodium chloride for injection, to a final concentration of 100 μg/ml.

Renal Impairment:

Epidural clonidine HCl must not 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.

HOW SUPPLIED

Duraclon is supplied in 100 μg/ml (0.1 mg/ml) and 500 μg/ml (0.5 mg/ml) strengths in 10 ml vials.

Storage:

DESCRIPTION

Catapres (clonidine hydrochloride) is a centrally acting antihypertensive agent available as tablets for oral administration in three dosage strengths: 0.1, 0.2, 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 HCl. It has the following molecular formula: C9H9Cl2N3.HCl, with molecular weight of 266.56.

Clonidine hydrochloride is an odorless, bitter, white, crystalline substance soluble in water and alcohol.

CLINICAL PHARMACOLOGY

Clonidine HCl acts relatively rapidly. The patient's blood pressure declines within 30-60 minutes after an oral dose, the maximum decrease occurring within 2-4 hours. The plasma level of clonidine HCl peaks in approximately 3-5 hours and the plasma half-life ranges from 12-16 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.

INDICATIONS AND USAGE

Clonidine HCl is indicated in the treatment of hypertension. Clonidine HCl may be employed alone or concomitantly with other antihypertensive agents.

CONTRAINDICATIONS

None known.

PRECAUTIONS

General

In patients who have developed localized contact sensitization to clonidine film, substitution of oral clonidine HCl 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 HCl substitution may elicit a similar reaction.

As with all antihypertensive therapy, clonidine HCl 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 HCl, the physician should reduce the dose gradually over 2-4 days withdrawal symptomatology.

An excessive rise in blood pressure following clonidine HCl 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 HCl.

Perioperative Use

Administration of clonidine HCl should be continued to within 4 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 the Patient

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 HCl therapy without a physician's advice.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

In a 132 week (fixed concentration) dietary administration study in rats, clonidine HCl administered at 32-46 times the maximum recommended daily human dose was unassociated with evidence of carcinogenic potential.

Fertility of male or female rats was unaffected by clonidine HCl doses as high as 150 μg/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 500-2000 μg/kg or 10-40 times the MRDHD.

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 HCl 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 μg/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 HCl is excreted in human milk, caution should be exercised when clonidine HCl is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in children have not been established.

DRUG INTERACTIONS

If a patient receiving clonidine HCl is also taking tricyclic antidepressants, the effect of clonidine may be reduced, thus necessitating an increase in dosage. Clonidine HCl 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 ANIMAL PHARMACOLOGY).

ADVERSE REACTIONS

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 in 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 HCl, but in many cases patients were receiving concomitant medication and a causal relationship has not been established.

Gastrointestinal:

Metabolic:

Central Nervous System:

Cardiovascular:

Dermatological:

Genitourinary:

Other:

OVERDOSAGE

The signs and symptoms of clonidine HCl 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 LD50 of clonidine in rats was 465 mg/kg, and in mice 206 mg/kg.

The general treatment of clonidine HCl 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 HCl, plasma clonidine levels were 60 ng/ml (1 hour), 190 ng/ml (1.5 hours), 370 ng/ml (2 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.

DOSAGE AND ADMINISTRATION

Adults

The dose of clonidine HCl must be adjusted according to the patient's individual blood pressure response. The following is a general guide to its administration.

Initial Dose:

Maintenance Dose:

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.

ANIMAL PHARMACOLOGY

In several studies, oral clonidine HCl produced a dose-dependent increase in the incidence and severity of spontaneously occurring retinal degeneration in albino rats treated for 6 months or longer. Tissue distribution studies in dogs and monkeys revealed that clonidine HCl 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 HCl 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 HCl did not alter retinal function as shown by specialized tests such as the electroretinogram and macular dazzle. In rats, clonidine HCl in combination with amitriptyline produced corneal lesions within 5 days.

HOW SUPPLIED

Catapres is supplied in tablets containing 0.1, 0.2, and 0.3 mg of clonidine HCl.

0.1 mg:

0.2 mg:

0.3 mg:

Storage:

DESCRIPTION

Transdermal Therapeutic System

Programmed delivery in vivo of 0.1, 0.2, or 0.3 mg clonidine per day, for 1 week.

Catapres-TTS (clonidine) is a transdermal system providing continuous systemic delivery of clonidine for 7 days at an approximately constant rate. Clonidine is a centrally acting alpha-agonist and is an antihypertensive agent. It is an imidazoline derivative whose chemical name is 2,6-dichloro-N-2-imidazolidinylidenebenzenamine.

System Structure and Components

Catapres-TTS is a multilayered film, 0.2 mm thick, containing clonidine as the active agent. System area is 3.5, 7.0, or 10.5 cm2 and the amount of drug released is directly proportional to area. (See Release Rate Concept.) The composition per unit area of all three dosages is identical.

Proceeding from the visible surface towards the surface attached to the skin, are four layers (1) a backing layer of pigmented polyester film; (2) a drug reservoir of clonidine, mineral oil, polyisobutylene, and colloidal silicon dioxide; (3) a microporous polypropylene membrane that controls the rate of delivery of clonidine from the system to the skin surface; (4) an adhesive formulation of clonidine, mineral oil, polyisobutylene, and colloidal silicon dioxide. Prior to use, a protective peel strip of polyester that covers layer 4 is removed.

Release Rate Concept

Clonidine film is programmed to release clonidine at an approximately constant rate for 7 days. The energy source for drug release derives from the concentration gradient existing between a saturated solution of drug in the system and the much lower concentration prevailing in the skin. Clonidine flows in the direction of the lower concentration at a constant rate, limited by the rate-controlling membrane, so long as a saturated solution is maintained in the drug reservoir.

Following system application to intact skin, clonidine in the adhesive layer saturates the skin sites below the system. Clonidine from the drug reservoir then begins to flow through the rate-controlling membrane and the adhesive layer of the system into the systemic circulation via the capillaries beneath the skin. Therapeutic plasma clonidine levels are achieved 2-3 days after initial application of clonidine film.

The 3.5, 7.0, and 10.5 cm2 systems respectively deliver 0.1, 0.2, and 0.3 mg clonidine per day. To ensure constant release of drug over 7 days, the total drug content of the system is greater than the total amount of drug delivered. Application of a new system to a fresh skin site at weekly intervals continuously maintains therapeutic plasma concentrations of clonidine. If the clonidine film is removed and not replaced with a new system, therapeutic plasma clonidine levels will persist for about 8 hours and than decline slowly over several days. Over this time period, blood plasma returns gradually to pretreatment levels. If the patient experiences localized skin irritation before completing 7 days of use, the system may be removed and replaced with a new one applied on a fresh skin site.

CLINICAL PHARMACOLOGY

Clonidine stimulates alpha-adrenoreceptors in the brain stem, resulting in reduced sympathetic outflow from the central nervous system and a decrease in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. Renal blood flow and glomerular filtration rate remain essentially unchanged. Normal postural reflexes are intact, and therefore orthostatic symptoms are mild and infrequent.

Acute studies with clonidine HCl in human have demonstrated a moderate reduction (15-20%) of cardiac output in the supine position with no change in the 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.

The plasma half-life of clonidine is 12.7 ± 7 hours. 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.

INDICATIONS AND USAGE

Clonidine film is indicated in the treatment of hypertension. It may be employed alone or concomitantly with other antihypertensive agents.

CONTRAINDICATIONS

Clonidine film should not be used in patients with known hypersensitivity to clonidine or to any other component of the adhesive layer of the therapeutic system.

PRECAUTIONS

General

In patients who have developed localized contact sensitization to clonidine film, substitution of oral clonidine HCl therapy may be associated with development of a generalized skin rash.

In patients who develop an allergic reaction to clonidine film that extends beyond the local patch site (such as generalized skin rash, urticaria, or angioedema) oral clonidine HCl substitution may elicit a similar reaction.

As with all antihypertensive therapy, clonidine film should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, or chronic renal failure.

Transdermal clonidine systems should be removed before attempting defibrillation or cardioversion because of the potential for altered electrical conductivity which may enhance the possibility of arcing, a phenomenon associated with the use of defibrillators.

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.

An excessive rise in blood pressure following clonidine film 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 cessation of clonidine film administration.

Perioperative Use

As with oral clonidine therapy, clonidine film therapy should not be interrupted during the surgical period. Blood pressure should be carefully monitored during surgery and additional measures to control blood pressure should be available if required. Physicians considering starting clonidine film therapy during the perioperative period must be aware that therapeutic plasma clonidine levels are not achieved until 2-3 days after initial application of clonidine film (see DOSAGE AND ADMINISTRATION).

Information for the Patient

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 film therapy without a physician's advice. Patients should be advised that if the system begins to loosen from the skin after application, the adhesive overlay should be applied directly over the system to ensure good adhesion over its 7 day lifetime. Instructions for using the system are provided. Patients who develop moderate or severe erythema and/or localized vesicle formation at the site of application, or a generalized skin rash, should consult their physician promptly about the possible need to remove the patch.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

In a 132 week (fixed concentration) dietary administration study in rats, clonidine HCl administered at 32-46 times the oral maximum recommended daily human dose (MRDHD) was unassociated with evidence of carcinogenic potential. Results from the Ames test with clonidine HCl reveled no evidence of mutagenesis. Fertility of male or female rats was unaffected by clonidine doses as high as 150 μg/kg or about 3 times the oral MRDHD. Fertility of female rats did, however, appear to be affected (in another experiment) at the dose levels of 500-2000 μg/kg or 10-40 times the oral MRDHD.

Pregnancy, Teratogenic Effects, Pregnancy Category C

Reproduction studies performed in rabbits at doses up to approximately 3 times the oral maximum recommended daily human dose (MRDHD) of clonidine HCl tablets have revealed no evidence of teratogenic or embryotoxic potential in rabbits. In rats, however, doses as low as 1/3 the MRDHD of clonidine 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 oral 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 the study was 500 μg/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 is excreted in human milk, caution should be exercised when clonidine film is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in children below the age of 12 have not been established.

DRUG INTERACTIONS

If a patient receiving clonidine is also taking tricyclic antidepressants, the effect of clonidine may be reduced, thus necessitating an increase in dosage. Clonidine 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 ANIMAL PHARMACOLOGY).

ADVERSE REACTIONS

Most systemic adverse effects during therapy with clonidine film have been mild and have tended to diminish with continued therapy. In a 3 month, multiclinic trial of clonidine film in 101 hypertensive patients, the most frequent systemic reactions were dry mouth (25 patients) and drowsiness (12 patients).

Transient localized skin reactions, primarily localized pruritus, occurred in 51 patients. Twenty-six (26) patients experienced localized erythema. This erythema and pruritus were more common in patients utilizing an adhesive overlay for the entire 7 day treatment period. Allergic contact sensitization to clonidine film was observed in 5 patients.

In additional clinical experience contact dermatitis resulting in treatment discontinuation was observed in 128 of 673 patients (about 19 in 100) after a mean duration of treatment of 37 weeks. The incidence in white females was about 34 in 100; in white males about 18 in 100; in black females about 14 in 100; and in black males about 8 in 100.

The following less frequent adverse experiences were also reported in patients involved in the multiclinic trial with clonidine film:

Gastrointestinal:

Central Nervous System:

Genitourinary:

Dermatological:

Oro-Otolaryngeal:

In addition, the following adverse reactions have been reported less frequently:

Gastrointestinal:

Metabolic:

Central Nervous System:

Cardiovascular:

Dermatological:

Genitourinary:

Other:

OVERDOSAGE

If symptoms of overdosage occur, remove all clonidine film systems. The signs and symptoms of clonidine 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 LD50 of clonidine in rats was 465 mg/kg, and in mice 206 mg/kg.

The general treatment of clonidine film overdosage may include 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 HCl, plasma clonidine levels were 60 ng/ml (1 hour), 190 ng/ml (1.5 hours), 370 ng/ml (2 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.

DOSAGE AND ADMINISTRATION

Apply clonidine film to a hairless area of intact skin on the upper arm or torso, once every 7 days. Each new application of clonidine film should be on a different skin site from the previous location. If the system loosens during 7 day wearing, the adhesive overlay should be applied directly over the system to ensure good adhesion.

To initiate therapy, clonidine film dosage should be titrated according to individual therapeutic requirements, starting with clonidine film 0.1 mg. If after 1 or 2 weeks the desired reduction in blood pressure is not achieved, increase the dosage by adding an additional clonidine film 0.1 mg or changing to a larger system. An increase in dosage above the two clonidine film 0.3 mg is usually not associated with additional efficacy.

When substituting clonidine film in patients on prior antihypertensive therapy, physicians should be aware that the antihypertensive effect of clonidine film may not commence until 2 to 3 days after initial application. Therefore, gradual reduction of prior drug dosage is advised. Some or all previous antihypertensive treatment may have to be continued, particularly in patients with more severe forms of hypertension.

ANIMAL PHARMACOLOGY

In several studies, oral clonidine HCl produced a dose-dependent increase in the incidence and severity of spontaneously occurring retinal degeneration in albino rats treated for 6 months or longer. Tissue distribution studies in dogs and monkeys revealed that clonidine HCl 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 HCl 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 HCl did not alter retinal function as shown by specialized tests such as the electroretinogram and macular dazzle.

In rats, clonidine HCl in combination with amitriptyline produced corneal lesions within 5 days.

HOW SUPPLIED

Catapres-TTS-1, Catapres-TTS-2 and Catapres-TTS-3 are supplied as 4 pouched systems and 4 adhesive overlays per carton. (See TABLE 2.)

Storage: