CLONIDINE HCI

Clonidine hydrochloride injection is a centrally-acting solution for use in continuous epidural infusion devices. Clonidine Hydrochloride, USP, is an imidazoline derivative and exists as a mesomeric compound. The chemical names are Benzenamine, 2, 6-dichloro-N-2-imidazolidinylidene monohydrochloride and 2-[(2,6-dichlorophenyl) imino]imidazolidine monohydrochloride. The following is the structural formula: Clonidine hydrochloride injection is supplied as a clear, colorless, preservative-free, pyrogen-free, aqueous sterile solution (pH 5 to 7) in 10 mL single-dose vials. Each mL of the 1000 mcg/10 mL (0.1 mg/mL) concentration contains 100 mcg of Clonidine Hydrochloride, USP and 9 mg Sodium Chloride, USP in Water for Injection, USP. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment. Each 10 mL vial contains 1mg (1000 mcg) of clonidine hydrochloride. Each mL of the 5000 mcg/10 mL (0.5 mg/mL) concentration contains 500 mcg of Clonidine Hydrochloride, USP and 9 mg Sodium Chloride, USP in Water for Injection, USP. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment. Each 10 mL vial contains 5 mg (5000 mcg) of clonidine hydrochloride. STRUCTURE

INDICATIONS & USAGE Clonidine hydrochloride is indicated in combination with opiates for the treatment of severe pain in cancer patients that is not adequately relieved by opioid analgesics alone. Epidural clonidine is more likely to be effective in patients with neuropathic pain than somatic or visceral pain (see CLINICAL PHARMACOLOGY : Clinical Trials). The safety of this drug product has only been established in a highly selected group of cancer patients, and only after an adequate trial of opioid analgesia. Other use is of unproven safety and is not recommended. In a rare patient, the potential benefits may outweigh the known risks (see WARNINGS ).

DOSAGE & ADMINISTRATION The recommended starting dose of clonidine hydrochloride injection 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. The 500 mcg/mL (0.5mg/mL) strength product must be diluted prior to use in 0.9% Sodium Chloride for Injection, USP, to a final concentration of 100 mcg/mL: Renal Impairment: 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. Clonidine hydrochloride injection 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. DOSAGE

Clonidine hydrochloride injection is contraindicated in patients with a history of sensitization or allergic reactions to clonidine. Epidural administration is contraindicated in the presence of an injection site infection, in patients on anticoagulant therapy, and in those with a bleeding diathesis. Administration of clonidine hydrochloride injection above the C4 dermatome is contraindicated since there are no adequate safety data to support such use (see WARNINGS ).

Adverse reactions seen during continuous epidural clonidine infusion are dose-dependent and typical for a compound of this pharmacologic class. The adverse events most frequently reported in the pivotal controlled clinical trial of continuous epidural clonidine administration consisted of hypotension, postural hypotension, decreased heart rate, rebound hypertension, dry mouth, nausea, confusion, dizziness, somnolence, and fever. Hypotension is the adverse event that most frequently requires treatment. The hypotension is usually responsive to intravenous fluids and, if necessary, appropriate parenterally-administered pressor agents. Hypotension was observed more frequently in women and in lower weight patients, but no dose-related response was established. Implantable epidural catheters are associated with a risk of catheter-related infections, including meningitis and/or epidural abscess. The risk depends on the clinical situation and the type of catheter used, but catheter related infections occur in 5%-20% of patients, depending on the kind of catheter used, catheter placement technique, quality of the catheter care, and length of catheter placement. The inadvertent intrathecal administration of clonidine has not been associated with a significantly increased risk of adverse events, but there are inadequate safety and efficacy data to support the use of intrathecal clonidine. Epidural clonidine was compared to placebo in a two week double-blind study of 85 terminal cancer patients with intractable pain receiving epidural morphine. The following adverse events were reported in two or more patients and may be related to administration of either clonidine hydrochloride injection or morphine. Incidence of Adverse Events in the Two-Week Trial An open label long-term extension of the above trial was performed. Thirty-two subjects received epidural clonidine and morphine for up to 94 weeks with a median dosing period of 10 weeks. The following adverse events (and percent incidence) were reported: hypotension/postural hypotension (47%); nausea (13%); anxiety/confusion (38%); somnolence (25%); urinary tract infection (22%); constipation, dyspnea, fever, infection (6% each); asthenia, hyperaesthesia, pain, skin ulcer, and vomiting (5% each). Eighteen percent of subjects discontinued this study as a result of catheter-related problems (infections, accidental dislodging, etc.), and one subject developed meningitis, possibly as a result of catheter-related infection. In this study, rebound hypertension was not assessed, and ECG and laboratory data not systematically sought. The following adverse reactions have also been reported with the use of any dosage form of clonidine. In many cases patients were receiving concomitant medication and a causal relationship has not been established: Body as a Whole: Weakness, 10%; fatigue, 4%; headache and withdrawal syndrome, each 1%. Also reported were pallor, a weakly positive Coomb’s test, and increased sensitivity to alcohol. Cardiovascular: Palpitations and tachycardia, and bradycardia, each 0.5%. Syncope, Raynaud’s phenomenon, congestive heart failure, and electrocardiographic abnormalities (i.e., sinus node arrest, functional bradycardia, high degree AV block) have been reported rarely. Rare cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis. Central Nervous System: Nervousness and agitation, 3%; mental depression, 1%; insomnia, 0.5%. Cerebrovascular accidents, other behavioral changes, vivid dreams or nightmares, restlessness, and delirium have been reported rarely. Dermatological: Rash, 1%; pruritus, 0.7%; hives, angioneurotic edema and urticaria, 0.5%; alopecia, 0.2%. Gastrointestinal: Anorexia and malaise, each 1%; mild transient abnormalities in liver function tests, 1%; hepatitis, parotitis, ileus and pseudo obstruction, and abdominal pain, rarely. Genitourinary: Decreased sexual activity, impotence, and libido, 3%; nocturia, about 1%; difficulty in micturition, about 0.2%; urinary retention, about 0.1%. Hematologic: Thrombocytopenia, rarely. Metabolic: Weight gain, 0.1%; gynecomastia, 1%; transient elevation of glucose or serum phosphatase, rarely. Musculoskeletal: Muscle or joint pain, about 0.6%; leg cramps, 0.3%. Oro-otolaryngeal: Dryness of the nasal mucosa was rarely reported. Ophthalmological: Dryness of the eyes, burning of the eyes and blurred vision were rarely reported. To report SUSPECTED ADVERSE REACTIONS, contact West-ward Pharmaceutical Corp. at 1-877-233-2001, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ADVERSE