DailyMed Label: Duraclon

DailyMed Label: Duraclon

2021

DailyMed Prescription

Duraclon

clonidine hydrochloride

Mylan Institutional LLC

NDC: 67457-218

NDC: 67457-218

Duraclon (clonidine hydrochloride injection, USP) is a centrally-acting analgesic 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: Duraclon (clonidine hydrochloride injection, USP) is supplied as a clear, colorless, preservative-free, pyrogen-free, aqueous sterile solution (pH 5 to 7) in single-dose, 10 mL vials. Each mL of the 100 mcg/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 1 mg (1000 mcg) of clonidine hydrochloride. Clonidine Hydrochloride Structural Formula

Duraclon 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 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 ).

The recommended starting dose of Duraclon 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 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. Duraclon 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. Discard unused portion.

Duraclon 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 Duraclon above the C4 dermatome is contraindicated since there are no adequate safety data to support such use (see WARNINGS ).

Cardiac Effects:  Epidural clonidine frequently causes decreases in heart rate. Symptomatic bradycardia can be treated with atropine. Rarely, atrioventricular block greater than first degree has been reported. Clonidine does not alter the hemodynamic response to exercise, but may mask the increase in heart rate associated with hypovolemia. Respiratory Depression and Sedation: Clonidine administration may result in sedation through the activation of alpha-adrenoceptors in the brainstem. High doses of clonidine cause sedation and ventilatory abnormalities that are usually mild. Tolerance to these effects can develop with chronic administration. These effects have been reported with bolus doses that are significantly larger than the infusion rate recommended for treating cancer pain. Depression:  Depression has been seen in a small percentage of patients treated with oral or transdermal clonidine. Depression commonly occurs in cancer patients and may be exacerbated by treatment with clonidine. Patients, especially those with a known history of affective disorders, should be monitored for the signs and symptoms of depression. Pain of Visceral or Somatic Origin:  In the clinical investigations, at doses tested, Duraclon was most effective in well-localized, ‘‘neuropathic’’ pain that was characterized as electrical, burning, or shooting in nature, and which was localized to a dermatomal or peripheral nerve distribution. Duraclon 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. Clonidine may potentiate the CNS-depressive effect of alcohol, barbiturates or other sedating drugs. Narcotic analgesics may potentiate the hypotensive effects of clonidine. Tricyclic anti-depressants may antagonize the hypotensive effects of clonidine. The effects of tricyclic anti-depressants 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. In a 132-week study in rats, clonidine hydrochloride administered as a dietary admixture at 5-8 times (based on body surface area) the 50 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 or female rats was unaffected by oral clonidine hydrochloride 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 hydrochloride doses up to approximately the MRDHD revealed no evidence of teratogenic or embryotoxic potential. In rats, however, doses as low as one-third the MRDHD were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating. Increased resorptions were not associated with treatment with the same or higher doses up to 0.5 times the MRDHD when dams were treated on days 6-15 of gestation. Increased resorptions were observed at higher levels (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 hydrochloride 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 Duraclon in obstetrical settings. Because maternal perfusion of the placenta is critically dependent on blood pressure, use of Duraclon 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 Duraclon in this limited indication and clinical population have been established in patients old enough to tolerate placement and management of an epidural catheter, based on evidence from adequate and well controlled studies in adults and experience with the use of clonidine in the pediatric age group for other indications. The use of Duraclon should be restricted to pediatric patients with severe intractable pain from malignancy that is unresponsive to epidural or spinal opiates or other more conventional analgesic techniques. The starting dose of Duraclon should be selected on per kilogram basis (0.5 mcg per kg per hour) and cautiously adjusted based on the clinical response.

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.

Clonidine may potentiate the CNS-depressive effect of alcohol, barbiturates or other sedating drugs. Narcotic analgesics may potentiate the hypotensive effects of clonidine. Tricyclic anti-depressants may antagonize the hypotensive effects of clonidine. The effects of tricyclic anti-depressants 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.

NDC 67457-218-10, 100 mcg/mL solution in 10 mL vials, packaged individually. Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Preservative Free. Discard unused portion. Duraclon ® is a registered trademark of Astellas US LLC, licensed to the Viatris Companies. Manufactured for: Mylan Institutional LLC Morgantown, WV 26505 U.S.A. Manufactured by: Mylan Institutional Galway, Ireland 0919L103 Revised: 3/2021 MI:DURAIJ:R6 To request medical information or to report suspected adverse reactions, contact Drug Safety at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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. 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 t 1 ⁄ 2 =11±9 minutes) followed by a slower elimination phase (t 1 ⁄ 2 =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. 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. Following an intravenous dose of 14 C-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 14 C-clonidine was given to subjects with varying degrees of kidney function, elimination half-lives varied (17.5 to 41 hours) as a function of creatinine clearance. In subjects undergoing hemodialysis only 5% of body clonidine stores were removed. In humans, clonidine metabolism follows minor pathways with the major metabolite, p-hydroxy-clonidine, being present at less than 10% of the concentration of unchanged drug in urine. 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 Duraclon 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 withdrawal of clonidine; one of these patients suffered a cerebrovascular accident. Asymptomatic bradycardia was noted in one clonidine patient.

NDC 67457-218-10     10 mL Duraclon ® (clonidine HCl injection, USP) 1000 mcg/10 mL (100 mcg/mL) For Epidural Injection Rx only Single-Dose Vial Preservative Free Sterile. Non-pyrogenic. Each mL contains: 100 mcg 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. Discard unused portion. Usual Dosage: See accompanying prescribing information. Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Manufactured for: Mylan Institutional LLC Morgantown, WV 26505 U.S.A. Made in Ireland 0511C103            MI:218:1C:R6 Duraclon ® is a registered trademark of Astellas US LLC, licensed to the Viatris Companies.. Mylan.com Duraclon (clonidine HCl injection, USP) 1000 mcg/10 mL (100 mcg/mL) - Carton Label