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CloNIDine

Pronunciation

Pronunciation

(KLON i deen)

Index Terms

  • Clonidine HCl
  • Clonidine Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Liquid Extended Release, Oral, as base:

Nexiclon XR: 0.09 mg/mL (118 mL [DSC]) [contains methylparaben, polysorbate 80, propylparaben]

Miscellaneous, Oral, as hydrochloride:

Kapvay: 0.1 mg AM dose, 0.2 mg PM dose (60 ea [DSC])

Patch Weekly, Transdermal:

Catapres-TTS-1: 0.1 mg/24 hr (4 ea)

Catapres-TTS-2: 0.2 mg/24 hr (4 ea)

Catapres-TTS-3: 0.3 mg/24 hr (4 ea)

Generic: 0.1 mg/24 hr (1 ea, 4 ea); 0.2 mg/24 hr (1 ea, 4 ea); 0.3 mg/24 hr (1 ea, 4 ea)

Solution, Epidural, as hydrochloride:

Duraclon: 100 mcg/mL (10 mL [DSC])

Generic: 100 mcg/mL (10 mL); 500 mcg/mL (10 mL)

Solution, Epidural, as hydrochloride [preservative free]:

Duraclon: 100 mcg/mL (10 mL)

Duraclon: 500 mcg/mL (10 mL) [pyrogen free]

Generic: 100 mcg/mL (10 mL); 500 mcg/mL (10 mL)

Tablet, Oral, as hydrochloride:

Catapres: 0.1 mg [scored; contains brilliant blue fcf (fd&c blue #1), corn starch, fd&c yellow #6 (sunset yellow)]

Catapres: 0.2 mg, 0.3 mg [scored; contains corn starch, fd&c yellow #6 (sunset yellow)]

Generic: 0.1 mg, 0.2 mg, 0.3 mg

Tablet Extended Release 12 Hour, Oral, as hydrochloride:

Kapvay: 0.1 mg

Generic: 0.1 mg

Tablet Extended Release 24 Hour, Oral, as base:

Nexiclon XR: 0.17 mg [DSC]

Brand Names: U.S.

  • Catapres
  • Catapres - TTS - 1
  • Catapres - TTS - 2
  • Catapres - TTS - 3
  • Duraclon
  • Kapvay
  • Nexiclon XR [DSC]

Pharmacologic Category

  • Alpha2-Adrenergic Agonist
  • Antihypertensive

Pharmacology

Stimulates alpha2-adrenoceptors in the brain stem, thus activating an inhibitory neuron, resulting in reduced sympathetic outflow from the CNS, producing a decrease in peripheral resistance, renal vascular resistance, heart rate, and blood pressure; epidural clonidine may produce pain relief at spinal presynaptic and postjunctional alpha2-adrenoceptors by preventing pain signal transmission; pain relief occurs only for the body regions innervated by the spinal segments where analgesic concentrations of clonidine exist. For the treatment of ADHD, the mechanism of action is unknown; it has been proposed that postsynaptic alpha2-agonist stimulation regulates subcortical activity in the prefrontal cortex, the area of the brain responsible for emotions, attentions, and behaviors and causes reduced hyperactivity, impulsiveness, and distractibility. 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.

Absorption

Oral: Extended release tablets (Kapvay) are not bioequivalent with immediate release formulations; peak plasma concentrations are 50% lower compared to immediate release formulations

Distribution

Vd: 2.9 L/kg (adults); highly lipid soluble; distributes readily into extravascular sites; Note: Epidurally administered clonidine readily distributes into plasma via the epidural veins and attains clinically significant systemic concentrations.

Metabolism

Extensively hepatic to inactive metabolites; undergoes enterohepatic recirculation

Excretion

Urine (40% to 60% as unchanged drug)

Onset of Action

Antihypertensive effect: Oral: Immediate release: 0.5 to 1 hour (maximum reduction in blood pressure: 2 to 4 hours); Transdermal: Initial application: 2 to 3 days

Attention-deficit/hyperactivity disorder: Oral: Extended release: Onset of action: 1 to 2 weeks (AAP 2011)

Time to Peak

Plasma: Oral: Immediate release: 1 to 3 hours; Extended release: 7 to 8 hours

Duration of Action

Oral: Immediate release: 6 to 10 hours

Half-Life Elimination

Neonates: 44 to 72 hours

Children: 8 to 12 hours

Adults: Normal renal function: 12 to 16 hours; Renal impairment: ≤41 hours

Epidural administration: CSF half-life elimination: 0.8 to 1.8 hours

Transdermal: Half-life elimination (after patch removal): ~20 hours (due to skin depot effect; increase in plasma clonidine concentrations may occur after patch removal [MacGregor 1985])

Protein Binding

20% to 40%

Special Populations: Renal Function Impairment

The half-life increases up to 41 hours in patients with severe renal impairment.

Use: Labeled Indications

Oral:

Immediate release: Management of hypertension (monotherapy or as adjunctive therapy)

Extended release (Kapvay): Treatment of attention-deficit/hyperactivity disorder (ADHD) (monotherapy or as adjunctive therapy)

Epidural (Duraclon): For continuous epidural administration as adjunctive therapy with opioids for treatment of severe cancer pain in patients tolerant to or unresponsive to opioids alone; epidural clonidine is generally more effective for neuropathic pain and less effective (or possibly ineffective) for somatic or visceral pain

Transdermal patch: Management of hypertension (monotherapy or as adjunctive therapy)

Note: According to the Eighth Joint National Committee (JNC 8) guidelines, clonidine is not recommended for the initial treatment of hypertension (James 2013). According to the AHA/ACC/ASH 2015 scientific statement for the treatment of hypertension in patients with coronary artery disease (CAD), clonidine should be avoided for the treatment of hypertension in patients with heart failure (with reduced ejection fraction) of ischemic origin (AHA/ACC/ASH [Rosendorff 2015]).

Use: Unlabeled

Heroin or nicotine withdrawal; severe pain; hot flashes; diabetes-associated diarrhea; impulse control disorder; clozapine-induced sialorrhea; aid in the diagnosis of growth hormone deficiency; attention-deficit/hyperactivity disorder (ADHD) and associated insomnia in children; Tourette's syndrome in children; aggression associated with conduct disorder

Contraindications

Hypersensitivity to clonidine hydrochloride or any component of the formulation

Epidural administration: Injection site infection; concurrent anticoagulant therapy; bleeding diathesis; administration above the C4 dermatome

Dosing: Adult

Note: Dosing is expressed as the salt (clonidine hydrochloride) unless otherwise noted. Formulations of clonidine (immediate release versus extended release) are not interchangeable on a mg:mg basis due to different pharmacokinetic profiles. Compounded oral suspensions may be available in multiple concentrations (up to 10-times more concentrated); precautions should be taken to verify and avoid confusion between the different concentrations; dose should be clearly presented as mcg or mg as appropriate.

Hypertension:

Oral: Immediate release: Initial dose: 0.1 mg twice daily (maximum recommended dose: 2.4 mg/day); usual dose range (ASH/ISH [Weber 2014]): 0.1 to 0.2 mg twice daily

Transdermal: Initial: 0.1 mg/24 hour patch applied once every 7 days and increase by 0.1 mg at 1- to 2-week intervals (dosages >0.6 mg/24 hours do not improve efficacy); usual dose range (ASH/ISH [Weber 2014]): 0.1 to 0.3 mg/24 hour patch applied once every 7 days

Acute hypertension (urgency) (off-label use): Oral: Initial 0.1 to 0.2 mg; may be followed by additional doses of 0.1 mg every hour, if necessary, to a maximum total dose of 0.7 mg (Atkin 1992; Jaker 1989)

Off-label route of administration: Sublingual: Initial: 0.1 to 0.2 mg; followed by 0.05 to 0.1 mg every hour until blood pressure controlled or a cumulative dose of 0.7 mg is reached (Cunningham 1994; Matuschka 1999)

Clozapine-induced sialorrhea (off-label use):

Oral: Initial: 0.05 mg at bedtime; if no improvement after 2 weeks, may increase to 0.1 mg at bedtime (Praharaj 2005)

Transdermal: 0.1 to 0.2 mg/24 hour patch applied once weekly (Grabowski 1992).

Note: Additional data may be necessary to further define the role of clonidine in this condition.

Nicotine withdrawal symptoms (off-label use) (Fiore 2008):

Oral: Initial: 0.1 mg twice daily; titrate by 0.1 mg/day every 7 days if needed; dosage range used in clinical trials: 0.15 to 0.75 mg/day; duration of therapy ranged from 3 to 10 weeks in clinical trials

Transdermal: Initial: 0.1 mg/24 hour patch applied once every 7 days and increase by 0.1 mg at 1-week intervals if necessary; dosage range used in clinical trials: 0.1 to 0.2 mg/24 hour patch applied once every 7 days; duration of therapy ranged from 3 to 10 weeks in clinical trials

Opioid withdrawal (off-label use): Oral: Immediate release: 0.1 to 0.3 mg every 6 to 8 hours (maximum: 1.2 mg/day) (Kampman [ASAM 2015])

Tourette syndrome (off-label use): Oral: Immediate release: Initial: 0.025 to 0.05 mg once daily; gradually increase dose based on response and tolerability up to a usual dosage of 0.1 to 0.6 mg/day in 3 to 4 divided doses (Murphy 2013; Pringsheim 2012; Roessner 2011).

Pain management: Epidural infusion: Reserved for cancer patients with severe intractable pain, unresponsive to other opioid analgesics: Starting dose: 30 mcg/hour; titrate as required for relief of pain or presence of side effects; experience with doses >40 mcg/hour is limited; should be considered an adjunct to opioid therapy

Conversion from oral to transdermal: Note: If transitioning from oral to transdermal therapy, overlap oral regimen for 1 to 2 days; transdermal route takes 2 to 3 days to achieve therapeutic effects. An example transition is below:

Day 1: Place Catapres-TTS 1; administer 100% of oral dose.

Day 2: Administer 50% of oral dose.

Day 3: Administer 25% of oral dose.

Day 4: Patch remains, no further oral supplement necessary.

Conversion from transdermal to oral: After transdermal patch removal, therapeutic clonidine levels persist for ~8 hours and then slowly decrease over several days. Consider starting oral clonidine no sooner than 8 hours after patch removal.

Dosing: Geriatric

Hypertension: Oral: Immediate release: Initial: 0.1 mg once daily at bedtime, increase gradually as needed.

Dosing: Pediatric

Note: Dosing is expressed as the salt (clonidine hydrochloride) unless otherwise noted. Formulations of clonidine (immediate release versus extended release) are not interchangeable on a mg:mg basis due to different pharmacokinetic profiles. Compounded oral suspensions may be available in multiple concentrations (up to 10-times more concentrated); precautions should be taken to verify and avoid confusion between the different concentrations; dose should be clearly presented as mcg or mg as appropriate.

Hypertension (off-label use): Oral: Children ≥12 years: Immediate release: Initial: 0.2 mg/day in 2 divided doses; increase gradually, if needed, in 0.1 mg/day increments at weekly intervals; maximum: 2.4 mg/day (rarely required) (NHBPEP, Fourth Report)

Severe hypertension (off-label use): Oral: Children: Immediate release: 0.05 to 0.1 mg/dose; may repeat up to a maximum total dose of 0.8 mg (NHBPEP, Fourth Report)

Clonidine tolerance test (test of growth hormone release from pituitary) (off-label use): Oral: Immediate release:

0.15 mg/m2 as a single dose (Lanes 1982)

or

5 mcg/kg as a single dose; maximum dose: 250 mcg (Richmond 2008)

ADHD: Oral: Note: May be used alone or as an adjunct to stimulants.

Immediate release (off-label indication; Pliszka 2007):

Children ≤45 kg: Initial: 0.05 mg at bedtime; sequentially increase every 3 to 7 days by 0.05 mg increments as twice daily, then 3 times daily, then 4 times daily; maximum daily dose: 0.2 mg/day for patients weighing 27 to 40.5 kg; 0.3 mg/day for patients weighing 40.5 to 45 kg. When discontinuing therapy, taper gradually over 1 to 2 weeks.

Children >45 kg: Initial: 0.1 mg at bedtime; sequentially increase every 3 to 7 days by 0.1 mg increments as twice daily, then 3 times daily, then 4 times daily; maximum daily dose: 0.4 mg/day. When discontinuing therapy, taper gradually over 1 to 2 weeks.

Extended release (Kapvay): Children ≥6 years: Initial: 0.1 mg at bedtime; increase in 0.1 mg/day increments every 7 days until desired response, doses should be administered twice daily in the morning and at bedtime (either split equally or with the higher split dosage given at bedtime); maximum daily dose: 0.4 mg/day. Note: When discontinuing therapy, taper daily dose by ≤0.1 mg every 3 to 7 days.

Conduct/oppositional-defiant disorder with or without ADHD (off-label use): Children ≥ 5 years and Adolescents: Oral: Immediate release: Initial: 0.05 mg/day; gradual titration every 3 to 7 days in 0.05 mg increments to 2 to 3 times daily schedule has been used most frequently, some patients may require 4 daily doses; usual final dose range: 0.2 to 0.3 mg/day in 2-3 divided doses, reported overall range: 0.15 to 0.4 mg/day in divided doses; most reported experience in patients with ADHD comorbidity (Connor 2000; Kemph 1993; Palumbo 2008). Additional data may be necessary to further define the role of clonidine in this condition.

Tourette syndrome (off-label use): Children ≥7 years and Adolescents: Oral: Immediate release: Initial: 0.025 to 0.05 mg once daily; gradually increase dose based on response and tolerability using small increments (0.025 mg) up to a usual dosage of 0.1 to 0.4 mg/day in 3 to 4 divided doses (Murphy 2013; Pringsheim 2012; Roessner 2011; The Tourette's Syndrome Study Group 2002). Note: Greater efficacy shown in patients with ADHD comorbidity (Weisman 2013).

Pain management: Epidural infusion: Reserved for cancer patients with severe intractable pain, unresponsive to other opioid analgesics: Initial: 0.5 mcg/kg/hour; adjust with caution, based on clinical effect

Dosing: Renal Impairment

Adults: Oral (immediate release), transdermal, epidural: The manufacturer recommends dosage adjustment according to degree of renal impairment; however, no specific dosage adjustment provided in manufacturer’s labeling. Bradycardia, sedation, and hypotension may be more likely to occur in patients with renal failure; half-life significantly prolonged in patients with severe renal failure; consider use of lower initial doses and monitor closely.

Children: Oral (extended release), epidural: The manufacturer recommends dosage adjustment according to degree of renal impairment; however, no specific dosage adjustment provided (has not been studied).

Hemodialysis: Not dialyzable (0% to 5%); supplemental dose is not necessary. Oral antihypertensive drugs given preferentially at night may reduce the nocturnal surge of blood pressure and minimize the intradialytic hypotension that may occur when taken the morning before a dialysis session (K/DOQI 2005).

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer’s labeling.

Reconstitution

Epidural formulation: Prior to administration, the 500 mcg/mL concentration must be diluted in 0.9% sodium chloride for injection (preservative-free) to a final concentration of 100 mcg/mL.

Extemporaneously Prepared

0.01 mg/mL concentration

A 0.01 mg/mL oral suspension may be made from tablets. Crush twenty 0.1 mg tablets in a glass mortar and reduce to a fine powder. Slowly add Ora-Blend in ~15 mL increments while mixing to form a uniform paste until approximately half of the total volume (~100 mL) is added. Transfer the suspension to a graduated cylinder. Rinse the mortar and pestle with the remaining vehicle and add quantity to fill the volume within the graduated cylinder to 200 mL. Transfer this amount to a calibrated bottle. Label “shake well”. When stored in clear plastic syringes, the suspension is stable for at least 91 days at room temperature (25°C) or refrigerated (4°C).

Ma C, Decarie D, Ensom MHH. Stability of clonidine oral suspension in oral plastic syringes. Am J Health-Syst Pharm. 2014;71:657-661.24688040

0.1 mg/mL concentration

A 0.1 mg/mL oral suspension may be made from tablets. Crush thirty 0.2 mg tablets in a glass mortar and reduce to a fine powder. Slowly add 2 mL Purified Water USP and mix to a uniform paste. Slowly add Simple Syrup, NF in 15 mL increments; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 60 mL. Label "shake well" and "refrigerate". Stable for 28 days when stored in amber glass bottles and refrigerated.

Levinson ML and Johnson CE. Stability of an extemporaneously compounded clonidine hydrochloride oral liquid. Am J Hosp Pharm. 1992;49(1):122-125.1570852

Administration

Epidural: Specialized techniques are required for continuous epidural administration; administration via this route should only be performed by qualified individuals familiar with the techniques of epidural administration and patient management problems associated with this route. Familiarization of the epidural infusion device is essential. Do not discontinue clonidine abruptly; if needed, gradually reduce dose over 2 to 4 days to avoid withdrawal symptoms.

Oral: May be taken with or without food. Do not discontinue clonidine abruptly. If needed, gradually reduce dose over 2-4 days to avoid rebound hypertension.

Extended release tablet: Kapvay: Swallow whole; do not crush, split, or chew.

Transdermal patch: Patches should be applied weekly at a consistent time to a clean, hairless area of the upper outer arm or chest. Rotate patch sites weekly. Redness under patch may be reduced if a topical corticosteroid spray is applied to the area before placement of the patch (Tom 1994). Dispose of any used or unused patches by folding adhesive ends together, replace in pouch or sealed container, and discard properly in trash away from children and pets.

Compatibility

Stable in NS

Storage

Epidural formulation: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Preservative free; discard unused portion.

Tablets: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Extended release tablets: Store at 20°C to 25°C (68°F to 77°F). Protect from light.

Transdermal patches: Store below 30°C (86°F).

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Analgesics (Opioid): CNS Depressants may enhance the CNS depressant effect of Analgesics (Opioid). Management: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Beta-Blockers: Alpha2-Agonists may enhance the AV-blocking effect of Beta-Blockers. Sinus node dysfunction may also be enhanced. Beta-Blockers may enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the Alpha2-Agonist is abruptly withdrawn. Management: Closely monitor heart rate during treatment with a beta blocker and clonidine. Withdraw beta blockers several days before clonidine withdrawal when possible, and monitor blood pressure closely. Recommendations for other alpha2-agonists are unavailable. Exceptions: Levobunolol; Metipranolol. Consider therapy modification

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Calcium Channel Blockers (Nondihydropyridine): CloNIDine may enhance the AV-blocking effect of Calcium Channel Blockers (Nondihydropyridine). Sinus node dysfunction may also be enhanced. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cardiac Glycosides: CloNIDine may enhance the AV-blocking effect of Cardiac Glycosides. Sinus node dysfunction may also be enhanced. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dimethindene (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

EPHEDrine (Systemic): CloNIDine may enhance the therapeutic effect of EPHEDrine (Systemic). Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Iobenguane I 123: Alpha2-Agonists may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methotrimeprazine: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylphenidate: May enhance the adverse/toxic effect of CloNIDine. Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: May diminish the antihypertensive effect of Alpha2-Agonists. Management: Consider avoiding concurrent use. If the combination cannot be avoided, monitor for decreased effects of alpha2-agonists if mirtazapine is initiated/dose increased, or increased effects if mirtazapine is discontinued/dose decreased. Consider therapy modification

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May diminish the antihypertensive effect of Alpha2-Agonists. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Tricyclic Antidepressants: May diminish the antihypertensive effect of Alpha2-Agonists. Consider therapy modification

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Test Interactions

Positive Coombs' test

Adverse Reactions

Frequency not always defined.

Oral, Transdermal: Incidence of adverse events may be less with transdermal compared to oral due to the lower peak/trough ratio.

>10%:

Central Nervous System: Drowsiness (2% to 38%), headache (1% to 29%), fatigue (4% to 16%), dizziness (2% to 16%)

Dermatologic: Transient skin rash (localized; characterized by pruritus and erythema; transdermal 15% to 50%), contact dermatitis (transdermal 8% to 34%)

Gastrointestinal: Xerostomia (≤40%), upper abdominal pain (15%)

1% to 10%:

Cardiovascular: Bradycardia (≤4%), edema (3%), localized blanching (transdermal 1%), palpitations (1%), tachycardia (≤3%), atrioventricular block, cardiac arrhythmia, cardiac failure, cerebrovascular accident, chest pain, ECG abnormality, flushing, orthostatic hypotension, prolonged Q-T Interval on ECG, Raynaud's phenomenon, syncope

Central Nervous System: Sedation (3% to 10%), irritability (5% to 9%), nightmares (4% to 9%), insomnia (≤6%), emotional disturbance (4%), lethargy (3%), nervousness (1% to 3%), depression (1%), throbbing (transdermal 1%), withdrawal syndrome (1%), aggressive behavior, agitation, anxiety, behavioral changes, delirium, delusions, hallucination (visual and auditory), malaise, numbness (localized; transdermal), paresthesia, parotid pain (oral), restlessness, vivid dream

Dermatologic: Localized vesiculation (transdermal 7%), allergic contact sensitivity (transdermal 5%), hyperpigmentation (transdermal 5%), burning sensation of skin (transdermal 3%), excoriation (transdermal 3%), macular eruption (1%), papule (transdermal 1%), alopecia, hypopigmentation (localized; transdermal), pallor, skin rash, urticaria

Endocrine & metabolic: Gynecomastia (1%), weight gain (<1%), decreased libido, hyperglycemia (transient; oral), increased thirst

Gastrointestinal: Constipation (1% to 10%), viral gastrointestinal infection (5%), anorexia (1%), abdominal pain (oral), diarrhea, gastrointestinal pseudo-obstruction (oral), nausea, parotitis (oral), sore throat, vomiting

Genitourinary: Urinary incontinence (4%), sexual disorder (3%), erectile dysfunction (2% to 3%), nocturia (1%), pollakiuria, urinary retention

Hematologic & oncologic: Thrombocytopenia (oral)

Hepatic: Abnormal hepatic function tests (mild transient abnormalities; <1%), hepatitis

Hypersensitivity: Angioedema

Neuromuscular & skeletal: Weakness (10%), tremor (1% to 4%), arthralgia (1%), myalgia (1%), leg cramps (<1%), increased creatine phosphokinase (transient; oral), limb pain

Ophthalmic: Accommodation disturbance, blurred vision, burning sensation of eyes, decreased lacrimation, dry eye syndrome, increased lacrimation

Otic: Otitis media (≤3%), otalgia

Respiratory: Asthma, dry nose, epistaxis, flu-like symptoms, nasal congestion, nasopharyngitis, respiratory tract infection, rhinorrhea

Miscellaneous: Crying (1% to 3%), fever

Epidural: Note: The following adverse events occurred more often than placebo in cancer patients with intractable pain being treated with concurrent epidural morphine.

>10%:

Cardiovascular: Hypotension (45%), orthostatic hypotension (32%)

Central nervous system: Confusion (13%), dizziness (13%)

Gastrointestinal: Xerostomia (13%)

1% to 10%:

Cardiovascular: Chest pain (5%)

Central nervous system: Hallucination (5%)

Dermatologic: Diaphoresis (5%)

Gastrointestinal: Nausea and vomiting (8%)

Otic: Tinnitus (5%)

ALERT: U.S. Boxed Warning

Epidural use:

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

Note: Epidural clonidine is not recommended for obstetrical, postpartum, or perioperative 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, postpartum or perioperative patient, potential benefits may outweigh the possible risks.

Warnings/Precautions

Concerns related to adverse effects:

• Bradycardia: May cause dose-dependent reductions in heart rate; use with caution in patients with preexisting bradycardia or those predisposed to developing bradycardia.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Hypotension: Symptomatic hypotension may occur with use. In all patients, use epidural clonidine with caution due to the potential for severe hypotension, especially in women and those of low body weight. Most hypotensive episodes occur within the first 4 days of initiation; however, episodes may occur throughout the duration of therapy.

• Respiratory depression: Epidural administration may result in mild respiratory depression (usually associated with higher than recommended doses).

• Xerostomia: May cause significant xerostomia.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with severe coronary insufficiency, including recent MI and conduction disturbances, including sinus node dysfunction. The use of epidural clonidine frequently reduces heart rate; AV block greater than first-degree has been reported rarely. Epidural clonidine is not recommended for use in patients with severe cardiovascular disease or hemodynamic instability. May lead to cardiovascular instability (hypotension, bradycardia).

• Cerebrovascular disease: Use with caution in patients with cerebrovascular disease.

• Renal impairment: Use with caution in patients with chronic renal impairment. The hemodynamic effects may be prolonged in those with renal impairment; elimination half-life significantly prolonged (up to 41 hours) in patients with severe renal impairment.

Concurrent drug therapy issues:

• Agents with SA/AV nodal blocking properties: Use with caution in patients concurrently receiving agents known to reduce SA node function and/or AV nodal conduction (eg, digoxin, diltiazem, metoprolol, verapamil); may increase risk of serious bradycardia.

• CNS depressants: Sedating effects may be potentiated when used with other CNS-depressant drugs or ethanol.

Special populations:

• Pediatric: Since children commonly have gastrointestinal illnesses with vomiting, they are susceptible to hypertensive episodes due to abrupt inability to take oral medication. Epidural clonidine should be reserved for pediatric cancer patients with severe intractable pain, unresponsive to other analgesics or epidural or spinal opioids.

• Surgical patients: Discontinue oral immediate release formulations within 4 hours of surgery then restart as soon as possible afterwards. Discontinue oral extended release formulations up to 28 hours prior to surgery, then restart the following day.

Dosage form specific issues:

• Epidural use: [US Boxed Warning]: Must dilute concentrated epidural injectable (500 mcg/mL) solution prior to use. Epidural clonidine is not recommended for perioperative, obstetrical, or postpartum pain due to risk of hemodynamic instability. Should be administered via continuous epidural infusion device. Monitor closely for catheter-related infection such as meningitis or epidural abscess.

• Product interchangeability: Oral formulations of clonidine (immediate release versus extended release) are not interchangeable on a mg:mg basis due to different pharmacokinetic profiles.

• Transdermal patch: May contain conducting metal (eg, aluminum); remove patch prior to MRI. Due to the potential for altered electrical conductivity, remove transdermal patch before cardioversion or defibrillation. Localized contact sensitization to the transdermal system has been reported; in these patients, allergic reactions (eg, generalized rash, urticaria, angioedema) have also occurred following subsequent substitution of oral therapy.

Other warnings/precautions:

• Contact lens wearers: Clonidine may cause eye dryness in patients who wear contact lenses.

• Discontinuation of therapy: Gradual withdrawal is needed (taper oral immediate release or epidural dose gradually over 2 to 4 days to avoid rebound hypertension) if drug needs to be stopped. Patients should be instructed about abrupt discontinuation (causes rapid increase in BP and symptoms of sympathetic overactivity). In patients on both a beta-blocker and clonidine where withdrawal of clonidine is necessary, withdraw the beta-blocker first and several days before clonidine withdrawal, then slowly decrease clonidine. In children and adolescents, extended release formulation (Kapvay) should be tapered in decrements of no more than 0.1 mg every 3 to 7 days. The clonidine withdrawal syndrome is more pronounced after abrupt cessation of long-term therapy than after short-term therapy (1 to 2 months). It has usually been associated with previous administration of high oral doses (>1.2 mg daily in adults) and/or continuation of beta-blocker therapy. The danger of abrupt discontinuation may be increased in patients with hypertension and/or other cardiovascular considerations. Blood pressure may increase 8 to 24 hours after last dose, but has occurred 60 hours after the last clonidine dose. Rebound hypertension has occurred with discontinuation of transdermal and epidural clonidine.

Monitoring Parameters

Blood pressure, standing and sitting/supine, mental status, heart rate

When used for the treatment of ADHD, thoroughly evaluate for cardiovascular risk. Monitor heart rate, blood pressure (when started and weaned), and consider obtaining ECG prior to initiation (Vetter 2008).

Clonidine tolerance test: In addition to growth hormone concentrations, monitor blood pressure and blood glucose (Huang 2001).

Epidural: Carefully monitor infusion pump; inspect catheter tubing for obstruction or dislodgement to reduce risk of inadvertent abrupt withdrawal of infusion. Monitor closely for catheter-related infection (eg, meningitis or epidural abscess).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Clonidine crosses the placenta; concentrations in the umbilical cord plasma are similar to those in the maternal serum and concentrations in the amniotic fluid may be 4 times those in the maternal serum. The pharmacokinetics of clonidine may be altered during pregnancy (Buchanan 2009). Untreated chronic maternal hypertension is associated with adverse events in the fetus, infant, and mother. If treatment for hypertension during pregnancy is needed, other agents are preferred (ACOG 2012). [U.S. Boxed Warning]: Epidural clonidine is not recommended for obstetrical or postpartum pain due to risk of hemodynamic instability.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dry mouth, constipation, fatigue, headache, nausea, loss of strength and energy, insomnia, nightmares, lack of appetite, abdominal pain, irritability, sweating a lot, vomiting, or tinnitus. Have patient report immediately to prescriber severe dizziness, passing out, bradycardia, tachycardia, abnormal heartbeat, contact lens discomfort, severe skin irritation, skin discoloration, skin redness, burning of skin, difficulty breathing, slow breathing, or shallow breathing (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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