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.
Note: Safety: Do not discontinue therapy abruptly. When discontinuing, taper gradually to decrease risk of withdrawal symptoms (eg, rebound hypertension) (see "Discontinuation of Therapy" below for additional information). Dosage forms: Oral doses are expressed as clonidine hydrochloride, whereas transdermal patch doses are expressed as clonidine base. Accordingly, due to differences in bioavailability, oral doses cannot be converted directly to a transdermal patch. For conversions, see "Transitioning Between Dosage Forms" below. In addition, immediate-release tablets should not be interchanged with extended-release formulations due to different pharmacokinetic profiles.
Hypertension, chronic (alternative agent):
Note: Not recommended for initial management but may be considered as additional therapy for resistant hypertension in patients who do not respond adequately to combination therapy with preferred agents (Ref). For severe asymptomatic hypertension, may consider short-term oral use for BP lowering (eg, over hours) if there is concern that severe BP elevation will precipitate an acute cardiovascular event, such as in patients with known aortic or intracranial aneurysms (Ref).
Oral:
Immediate release: Initial: 0.1 mg twice daily; increase dose in increments of 0.1 mg/day at weekly intervals based on response and tolerability; patients with severe asymptomatic hypertension and no signs of acute end organ damage should be evaluated for medication adjustment within 1 week (Ref); usual dose range: 0.2 to 0.6 mg/day in 2 divided doses. The manufacturer's labeling includes a maximum daily dose of 2.4 mg; however, doses >0.6 mg/day are generally not used.
Extended release (Nexiclon): Initial: 0.17 mg once daily at bedtime; increase dose in increments of 0.09 mg/day at weekly intervals based on response and tolerability; usual dose range: 0.17 to 0.52 mg once daily; maximum dose: 0.52 mg/day.
Transdermal: Initial: 0.1 mg per 24-hour patch applied once every 7 days; increase by 0.1 mg at 1- to 2-week intervals; usual dose range: 0.1 to 0.3 mg per 24-hour patch applied once every 7 days. Onset of effect is delayed for 2 to 3 days following initial application.
Note: In patients undergoing surgery, maintenance dose is generally continued perioperatively to avoid rebound hypertension associated with abrupt withdrawal. ER tablets (Nexiclon) may be administered up to 28 hours prior to surgery and resumed the following day. It may be appropriate to transition to a transdermal patch ≥3 days before surgery in select patients who are not expected to resume enteral medication ≤12 hours after surgery. See "Transitioning Between Dosage Forms" below (Ref).
ICU sedation, transition from dexmedetomidine to clonidine (off-label use):
Note: Consider use in patients who are hemodynamically stable and able to receive medications enterally. Monitor blood pressure and heart rate during initiation and transition (Ref).
Oral: Immediate release:
Initial: Note: Decrease dexmedetomidine dose by 25% within 6 hours of each clonidine dose. Dexmedetomidine can usually be stopped within 48 hours.
Dexmedetomidine dose <0.7 mcg/kg/hour: 0.1 to 0.2 mg every 6 to 8 hours (Ref).
Dexmedetomidine dose ≥0.7 mcg/kg/hour: 0.3 mg every 6 to 8 hours (Ref).
Maintenance: Titrate to achieve target sedation levels to a usual dosage range of 0.2 to 0.5 mg every 6 hours (Ref). Gradually taper clonidine by extending the dosing interval every 24 to 48 hours (Ref).
Opioid withdrawal, medically supervised (adjunctive or alternative agent) (off-label use):
Note: Adjunct to opioid agonist for relief of withdrawal symptoms. May also be used as primary treatment when opioid agonist therapy is not indicated or not available. May be combined with other adjunctive medications as needed. To assess severity of withdrawal symptoms and adjust therapy, the use of a standard instrument for scoring of clinical observations (eg, Clinical Opioid Withdrawal Scale) is suggested (Ref).
Oral: Immediate release:
Initial: 0.1 to 0.2 mg (patients >90 kg may receive up to 0.3 mg); may repeat every 45 to 60 minutes if needed, up to a total of 4 doses until symptoms resolve, provided blood pressure and heart rate remain stable; maximum dose: typically, 0.8 mg/day or up to 1.2 mg/day for patients >90 kg (Ref).
Maintenance: 0.1 to 0.3 mg every 6 to 8 hours determined by symptom severity; maximum dose: 1.2 mg/day in divided doses (Ref).
Note: After a stable oral dose is established, may transition to an equivalent dose of a transdermal patch (see "Transitioning between dosage forms" below); according to some institutional protocols, may initiate therapy with a transdermal patch in select patients (Ref).
Vasomotor symptoms associated with menopause (alternative agent):
Note: May consider use when menopausal hormonal therapy is contraindicated and when other nonhormonal therapies are ineffective or not tolerated. Side effects (eg, dry mouth, dizziness, constipation, hypotension, sedation) may limit use. Transdermal administration may provide more stable serum concentrations to help limit side effects (Ref).
Oral : Immediate release: 0.05 mg twice daily; discontinue treatment if no improvement after 2 to 4 weeks (Canadian manufacturer's labeling). Some experts recommend upward titration based on response and tolerability to a dosage range of 0.1 to 1 mg/day in divided doses (Ref).
Transdermal (off label): Initial: 0.1 mg/24-hour patch applied once every 7 days; increase to 0.2 mg/24-hour patch then 0.3 mg/24-hour patch based on response and tolerability (Ref).
Transitioning between dosage forms:
Transition from IR tablets to ER (Nexiclon) tablets:
0.05 mg twice daily of immediate release is equivalent to 0.09 mg once daily of extended release (Nexiclon).
0.1 mg twice daily of immediate release is equivalent to 0.17 mg once daily of extended release (Nexiclon).
0.2 mg twice daily of immediate release is equivalent to 0.34 mg once daily of extended release (Nexiclon).
0.3 mg twice daily of immediate release is equivalent to 0.52 mg once daily of extended release (Nexiclon).
Transition from oral to transdermal: Note: If transitioning from oral to transdermal therapy, overlap oral regimen for 1 to 3 days; transdermal route takes 2 to 3 days to achieve therapeutic effect.
An example transition is below:
Day 1: Place transdermal patch; administer 100% of oral dose.
Day 2: Patch remains; administer 50% of oral dose.
Day 3: Patch remains; administer 25% of oral dose.
Day 4: Patch remains; no further oral dosing.
Transition from transdermal to oral: After transdermal patch removal, therapeutic clonidine levels persist for ~8 hours and then slowly decrease over several days, with a potential for continued effect for 24 to 48 hours after removal. A persistent effect on blood pressure should be considered when restarting oral clonidine. Consider starting oral clonidine no sooner than 8 hours after patch removal (Ref).
Discontinuation of therapy: Do not stop oral therapy abruptly to decrease risk of rebound hypertension and other withdrawal symptoms (eg, nervousness, agitation, headache, tremor); discontinue slowly over 6 to 10 days by reducing the dose by one-third to one-half every 2 to 3 days. For patients on both a beta-blocker and clonidine, withdraw the beta-blocker several days before clonidine, then slowly taper clonidine. Rebound hypertension and withdrawal symptoms are less likely with a transdermal patch compared to oral therapy (Ref). Note: Clonidine administration is generally not interrupted during the perioperative period (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Clonidine is excreted primarily through the kidneys as unchanged drug (40% to 60%). For this reason, dose initiation and titration should be done cautiously with monitoring of response in patients with significant kidney impairment (Ref). Additionally, patients with advanced kidney impairment may have impaired alpha-adrenergic responsiveness (Ref); individualize dose according to patient response.
Altered kidney function:
Oral, transdermal:
eGFR >30 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR <30 mL/minute/1.73 m2: Start with a low dose and titrate upward cautiously according to patient response, no more frequently than for patients with normal kidney function; monitor BP and heart rate closely (Ref).
Hemodialysis, intermittent (thrice weekly): Minimally dialyzable (0% to 5%):
ER tablet (Kapvay), IR tablet, transdermal: Start with a low dose and titrate upward cautiously according to patient response, no more frequently than for patients with normal kidney function; monitor BP and heart rate closely (Ref); no supplemental dose postdialysis is necessary (Ref).
ER tablet (Nexiclon): Initiate at 0.09 mg once daily at bedtime; titrate upward cautiously.
Peritoneal dialysis: Unlikely to be significantly dialyzable (highly lipid soluble) (Ref):
Oral, transdermal: Start with a low dose and titrate upward cautiously according to patient response, no more frequently than for patients with normal kidney function; monitor BP and heart rate closely (Ref).
CRRT:
Oral: Initial: Start with a low dose and titrate upward cautiously according to patient response, no more frequently than for patients with normal kidney function; monitor BP and heart rate closely (Ref).
Transdermal: Avoid use (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration):
Oral: Initial: Start with a low dose and titrate upward cautiously according to patient response, no more frequently than for patients with normal kidney function; monitor BP and heart rate closely (Ref).
Transdermal: Avoid use (Ref).
No dosage adjustment provided in manufacturer's labeling.
(For additional information see "Clonidine: Pediatric drug information")
Note: Safety: To avoid adverse effects (eg, rebound hypertension), do not discontinue clonidine abruptly. Dosing is expressed as the salt (clonidine hydrochloride) unless otherwise noted. Extemporaneously compounded oral suspensions are available in multiple concentrations (eg, 0.01 mg/mL, 0.02 mg/mL, 0.1 mg/mL); precautions should be taken to verify and avoid confusion between the different concentrations; dose should be clearly presented as mcg or mg as appropriate (ie, not in mL or number of tablets). Dosage forms: Immediate-release (tablets) vs extended-release (Kapvay [tablets], Nexiclon XR [tablets]) formulations of clonidine are not interchangeable on a mg per mg basis due to different pharmacokinetic profiles. Extended-released formulations (Kapvay [tablets] vs Nexiclon XR [tablets]) are not interchangeable on a mg:mg basis; only Kapvay is approved for use in pediatric patients. Transdermal patch is a membrane-controlled system; do not cut the patch to deliver partial doses; if cut, rate of drug delivery, reservoir contents, and adhesion may be affected; if partial dose is needed, surface area of patch can be blocked proportionally using adhesive bandage (Ref).
Attention-deficit/hyperactivity disorder (ADHD) (alternative or adjunctive agent):
Note: May be used as monotherapy or as an adjunct to stimulant therapy (Ref). May be optimal for patients with comorbid tics or Tourette syndrome, a history of psychosis or mania, or emotional dysregulation (Ref).
Oral:
Immediate release: Limited data available:
Children ≥6 years and Adolescents (Ref):
Weight 27 to 40.5 kg: Oral: Initial: 0.05 mg at bedtime; sequentially increase as tolerated every 2 to 3 days in 0.05 mg/day increments given as 0.05 mg twice daily, then 3 times daily, then 4 times daily; maximum daily dose: 0.2 mg/day. Note: Dosing interval of twice daily or 3 times daily preferred by some experts for ease of dosing and increased compliance. When discontinuing therapy, taper over 1 to 2 weeks.
Weight >40.5 to 45 kg: Oral: Initial: 0.05 mg at bedtime; sequentially increase as tolerated every 2 to 3 days in 0.05 mg/day increments given as 0.05 mg twice daily, then 3 times daily, then 4 times daily; maximum daily dose: 0.3 mg/day. Note: Dosing interval of twice daily or 3 times daily preferred by some experts for ease of dosing and increased compliance. When discontinuing therapy, taper over 1 to 2 weeks.
Weight >45 kg: Oral: Initial: 0.1 mg at bedtime; sequentially increase as tolerated every 2 to 3 days in 0.1 mg/day increments given as 0.1 mg twice daily, then 3 times daily, then 4 times daily; maximum daily dose: 0.4 mg/day. Note: Dosing interval of twice daily or 3 times daily preferred by some experts for ease of dosing and increased compliance. When discontinuing therapy, taper over 1 to 2 weeks.
Extended-release tablets (eg, Kapvay or associated generics): Children ≥6 years and Adolescents: Oral: Initial: 0.1 mg at bedtime; increase as tolerated in 0.1 mg/day increments every 7 days until desired response; after initial dose, 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 (Ref).
Topical: Transdermal patch: Limited data available: Children ≥6 years and Adolescents: May be converted to the transdermal delivery system after oral therapy is titrated to an optimal and stable dose; a transdermal dose approximately equivalent to the total oral daily dose may be used; apply transdermal patch and change every 5 to 7 days. Adjustment of transdermal patch dose may be needed; there is variation in absorption and no exact equivalence or fixed ratio exist between the oral and transdermal routes (Ref).
Growth hormone deficiency test: Limited data available: Children and Adolescents: Oral: Immediate release: 5 mcg/kg or 150 mcg/m2 as a single dose; maximum dose: 250 mcg/dose (Ref).
Hypertension (alternative agent ):
Acute severe hypertension with significant but not life-threatening symptoms (eg, severe headache, vomiting but no seizures): Limited data available: Children and Adolescents: Oral: Immediate release: 2 to 5 mcg/kg/dose; may repeat dose every 6 to 8 hours; maximum dose: 10 mcg/kg/dose up to a maximum total dose of 0.8 mg (Ref).
Chronic hypertension: Note: Clonidine is no longer recommended for primary use in children with chronic hypertension (Ref).
Insomnia, especially with neurodevelopmental disorders (alternative therapy): Limited data available:
Note: Most commonly used in patients with comorbid ADHD (Ref). The use of clonidine for insomnia in patients without neurodevelopmental disorders is based on expert clinical experience (limited/no published data); use should be reserved for patients who have failed nonpharmacologic interventions and in whom other underlying contributors have been identified and appropriately managed. When discontinuing, gradually reduce dose over 2 to 7 days (Ref):
Children ≥4 years and Adolescents: Immediate release:
Weight <27 kg: Oral: Initial: 25 to 50 mcg at bedtime; titrate in 25 mcg increments every 1 to 2 weeks as tolerated; usual daily dose: 5 to 10 mcg/kg/day; maximum daily dose: 10 mcg/kg/day (Ref).
Weight 27 to 40.5 kg: Oral: Initial: 25 to 50 mcg at bedtime; titrate in 25 mcg increments every 1 to 2 weeks as tolerated; maximum daily dose: 0.2 mg/day (Ref).
Weight >40.5 kg to 45 kg: Oral: Initial: 25 to 50 mcg at bedtime; titrate in 25 mcg increments every 1 to 2 weeks as tolerated; maximum daily dose: 0.3 mg/day (Ref).
Weight >45 kg: Oral: Initial: 25 to 50 mcg at bedtime; titrate in 25 mcg increments every 1 to 2 weeks as tolerated; maximum daily dose: 0.4 mg/day (Ref).
Posttraumatic stress disorder (PTSD): Very limited data available:
Children 5 to ≤10 years: Oral: Immediate release: Initial: 0.05 mg at bedtime; may titrate in 0.05 mg increments every 3 days; reported target dose: 0.2 to 0.5 mg/day; the total daily dose should be divided into multiple doses per day due to the short half-life (Ref); 3-times-daily dosing has been reported (Ref); maximum daily dose: 0.5 mg/day (Ref).
Children >10 years and Adolescents: Oral: Immediate release: Initial: 0.1 mg at bedtime; may titrate in 0.05 mg increments every 3 days; reported target dose: 0.2 to 0.5 mg/day; the total daily dose should be divided into multiple doses per day due to the short half-life (Ref); 3-times-daily dosing has been reported (Ref); maximum daily dose: 0.5 mg/day (Ref).
Tic disorders and Tourette syndrome: Limited data available:
Note: Efficacy results variable; compared to placebo, clonidine may be more likely to reduce tic severity, with largest effects observed in patients with comorbid ADHD (Ref):
Children ≥7 years and Adolescents: Oral: Immediate release: Initial: 0.025 to 0.05 mg/day in 1 to 2 divided doses; gradual titration to a 3- to 4-times-daily schedule using small increments (0.025 mg); usual daily dose: 0.1 to 0.4 mg/day in 3 to 4 divided doses; reported maximum daily dose: 0.6 mg/day (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Children and Adolescents: Oral: Extended release (eg, Kapvay): The manufacturer recommends dosage adjustment according to degree of renal impairment; however, there are no specific dosage adjustment provided in the labeling (has not been studied). Bradycardia, sedation, and hypotension may be more likely to occur in patients with renal failure; drug is primarily eliminated unchanged in the urine; consider using doses at the lower end of the dosage range; monitor patients closely.
Hemodialysis: Not dialyzable (0 to 5%); supplemental dose is not necessary.
There are no dosage adjustments provided in the manufacturer's labeling.
Hypertension: Oral:
Extended release: Consider initiating at a lower dose.
Immediate release: Initial: 0.1 mg once daily at bedtime, increase gradually as needed.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
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 [preservative free]:
Duraclon: 100 mcg/mL (10 mL)
Generic: 100 mcg/mL (10 mL); 500 mcg/mL (10 mL)
Tablet, Oral, as hydrochloride:
Catapres: 0.1 mg [DSC] [scored; contains corn starch, fd&c blue #1 (brilliant blue), fd&c yellow #6 (sunset yellow)]
Catapres: 0.2 mg [DSC], 0.3 mg [DSC] [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 hydrochloride:
Nexiclon XR: 0.17 mg [scored]
Generic: 0.17 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Generic: 0.025 mg
Tablet, Oral, as hydrochloride:
Generic: 0.1 mg, 0.2 mg
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 3 days to avoid withdrawal symptoms.
Oral: May be taken with or without food. Swallow whole with water (0.025 mg tablet [Canadian product]). Swallow ER tablets (Kapvay) whole; do not crush, chew, or split. ER tablets (Nexiclon) are scored tablets and may be split in half. Administer ER tablets (Nexiclon) preferably at bedtime.
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 (Ref). 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.
Oral: May be administered without regard to meals. Swallow extended-release formulations whole; do not crush or chew. Kapvay should not be split. Do not discontinue clonidine abruptly.
Transdermal: Patches should be applied at bedtime to a clean, hairless area of the upper arm or chest. In adults, patches are applied every 7 days, rotating patch sites weekly; in children, the patch may need to be changed more frequently (eg, every 5 days) (Ref); in adults, redness under patch may be reduced if a topical corticosteroid spray is applied to the area before placement of the patch (Ref); Note: Transdermal patch is a membrane-controlled system; do not cut the patch to deliver partial doses; rate of drug delivery, reservoir contents, and adhesion may be affected if cut; if partial dose is needed, surface area of patch can be blocked proportionally using adhesive bandage (Ref).
Epidural: Not for IV use. Visually inspect for particulate matter and discoloration prior to administration (whenever permitted by container and solution). 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.
Attention-deficit/hyperactivity disorder (ER tablet [Kapvay]): Treatment of attention-deficit/hyperactivity disorder (monotherapy or as adjunctive therapy).
Hypertension, chronic (ER tablet [Nexiclon], IR tablet, and transdermal patch): Management of hypertension.
Vasomotor symptoms associated with menopause (0. 025 mg tablet [ Canadian product]): Relief of menopausal flushing in patients for whom hormonal replacement therapy is unnecessary or not desirable.
ICU sedation, transition from dexmedetomidine to clonidine; Opioid withdrawal, medically supervised; Vasomotor symptoms associated with menopause
CloNIDine may be confused with Clomid, clomiPHENE, clonazePAM, cloZAPine, KlonoPIN, quiNIDine
Catapres may be confused with Cataflam, Combipres
The Institute for Safe Medication Practices (ISMP) includes this medication (epidural administration) among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Beers Criteria: Clonidine is identified in the Beers Criteria as a potentially inappropriate medication in patients 65 years and older (independent of diagnosis or condition) for hypertension treatment due to high risk of CNS adverse effects and risk of bradycardia and orthostatic hypotension associated with central alpha blockers. Avoid clonidine as a first-line antihypertensive (Beers Criteria [AGS 2019]).
Use caution when interpreting dosing information. Pediatric dose for epidural infusion expressed as mcg/kg/hour.
Transdermal patch may contain conducting metal (eg, aluminum); remove patch prior to MRI. Errors have occurred when the inactive, optional adhesive cover has been applied instead of the active clonidine-containing patch.
Bradycardia and hypotension may occur with therapeutic or supratherapeutic dosing of clonidine in all ages. These adverse reactions may require intervention, and they are generally reversible with discontinuation.
Mechanism: Dose-related (consistently with bradycardia; more variable with hypotension); related to the pharmacologic action (ie, central alpha-2 adrenergic receptor agonist-mediated reduction in sympathetic outflow) (Ref).
Onset: Varied; may occur at any time during therapy. Varies based on dosage form (Ref). May occur within 30 minutes of oral administration (most significant effects within 1 to 4 hours) (Ref). There is a 2- to 3-day delay in onset for transdermal administration (Ref). Most hypotensive episodes occur within the first 4 days with epidural administration (Ref).
Risk factors:
Hypotension:
• Concurrent antihypertensives or antipsychotics
• History of bradycardia, dehydration, hypotension, or syncope
• Perioperative use (Ref)
• Transdermal preparations in the setting of a degraded skin barrier and excessive dosing (Ref)
• Epidural administration
- Concurrent narcotic analgesics
- Females
- Hemodynamic instability
- Low body weight
- Severe cardiovascular disease
- Use in obstetrical or postpartum patients
Bradycardia:
• Cardiac conduction abnormalities
• Clinical sinus node dysfunction (Ref)
• Concurrent administration of medications that impact sinus node function or AV node conduction (eg, beta-blockers, digoxin, diltiazem, verapamil)
• History of bradycardia, or dehydration, hypotension, or syncope
• Kidney impairment (Ref)
• Patients who develop bradycardia while taking other sympatholytic medications or who are concurrently taking another sympatholytic medication (Ref)
• Perioperative use (Ref)
• Transdermal preparations in the setting of a degraded skin barrier and excessive dosing (Ref)
• Epidural administration
- Use in obstetrical or postpartum patients
A withdrawal syndrome, primarily characterized by a rapid increase in blood pressure (rebound hypertension), may occur upon abrupt discontinuation of clonidine, regardless of administration route. Additional symptoms may include diaphoresis, flushing, headache, and insomnia (Ref). Risk may be lower with transdermal clonidine administration due to a more gradual reduction in drug concentrations (Ref). Blood pressure may exceed pretreatment levels in some cases (Ref).
Mechanism: Withdrawal; result of excessive plasma catecholamine levels, “catecholamine surge” (Ref).
Onset: Rapid; typically occurs within 4 to 24 hours of drug discontinuation but may occur up to 72 hours after drug discontinuation (Ref).
Risk factors:
• Cardiovascular disease
• Concurrent cardioselective beta-blocker therapy
• Duration of use (>1 to 2 months) (Ref)
• Higher doses (>1 mg/day) (Ref)
• Hypertension
• Medication nonadherence
• Vomiting (abrupt inability to absorb oral dosage forms)
• Empty infusion pump drug reservoir (neuraxial administration)
• Infusion pump malfunction (neuraxial administration) (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Oral, Transdermal: Incidence of adverse reactions may be less with transdermal compared to oral due to the lower peak/trough ratio.
>10%:
Dermatologic: Contact dermatitis (transdermal: 8% to 34%), transient skin rash (localized; characterized by pruritus and erythema; transdermal: 50%)
Gastrointestinal: Upper abdominal pain (15%), xerostomia (5% to 40% [placebo: 1%])
Nervous system: Dizziness (2% to 16% [placebo: 5%]), drowsiness (12% to 38% [placebo: 4%]), fatigue (6% to 16% [placebo: 1%]), headache (1% to 20% [placebo: 16%])
1% to 10%:
Cardiovascular: Bradycardia (4% [placebo: 0%]), localized blanching (transdermal: 1%)
Dermatologic: Burning sensation of skin (transdermal: 3%), contact hypersensitivity (transdermal: 5%), excoriation of skin (transdermal: 3%), hyperpigmentation (transdermal: 5%), localized vesiculation (transdermal: 7%), macular eruption (transdermal: 1%), papule of skin (transdermal: 1%)
Gastrointestinal: Constipation (1% to 10%), dysgeusia (transdermal: 1%), nausea (1% to 5%), viral gastrointestinal infection (5%)
Genitourinary: Impotence (transdermal: ≤2%), sexual disorder (transdermal: ≤2%), urinary incontinence (4%)
Local: Localized edema (transdermal: 3%)
Nervous system: Aggressive behavior (1% to 3%), emotional disturbance (4%), insomnia (5% to 6% [placebo: 1%]), irritability (5% to 9%), lethargy (3%), nervousness (1%), night terrors (3%), nightmares (4% to 9%), restless sleep (3%), sedated state (3% to 10%), sleep disorder (1% to 3%), throbbing (transdermal: 1%)
Neuromuscular & skeletal: Tremor (1% to 4%)
Otic: Otitis media (3%; acute)
Respiratory: Dry throat (transdermal: 2%)
Miscellaneous: Crying (1% to 3%)
Frequency not defined:
Cardiovascular: Atrioventricular block, cardiac failure, cerebrovascular accident, chest pain, orthostatic hypotension, palpitations, prolonged QT interval on ECG, Raynaud's disease, syncope, tachycardia
Dermatologic: Alopecia, hypopigmentation (localized), pallor, skin rash, urticaria
Endocrine & metabolic: Increased serum glucose (transient), gynecomastia, loss of libido, weight gain
Gastrointestinal: Abdominal pain, anorexia, gastrointestinal pseudo-obstruction, parotitis, salivary gland pain, vomiting
Genitourinary: Breast hypertrophy, difficulty in micturition, erectile dysfunction, nocturia, urinary retention
Hematologic & oncologic: Positive direct Coombs test, thrombocytopenia
Hepatic: Abnormal hepatic function tests (mild; transient), hepatitis
Hypersensitivity: Angioedema
Nervous system: Agitation, anxiety, behavioral changes, decreased sexual activity, delirium, delusions, depression, hallucination (visual and auditory), malaise, numbness (localized), paresthesia, restlessness, vivid dream, withdrawal syndrome
Neuromuscular & skeletal: Arthralgia, asthenia, increased creatine phosphokinase in blood specimen (transient), lower limb cramp, myalgia
Ophthalmic: Accommodation disturbance, blurred vision, burning sensation of eyes, decreased lacrimation, dry eye syndrome
Respiratory: Dry nose
Miscellaneous: Fever, increased sensitivity to alcohol
Epidural: The following adverse reactions occurred more often than placebo in cancer patients with intractable pain being treated with concurrent epidural morphine.
>10%:
Cardiovascular: Hypotension (45% [placebo: 11%]), orthostatic hypotension (32% [placebo: 0%])
Gastrointestinal: Xerostomia (13% [placebo: 9%])
Nervous system: Confusion (13%), dizziness (13% [placebo: 4%])
1% to 10%:
Cardiovascular: Chest pain (5%)
Dermatologic: Diaphoresis (5% [placebo: 0%])
Gastrointestinal: Nausea and vomiting (8%)
Nervous system: Hallucination (5%)
Otic: Tinnitus (5%)
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.
Canadian labeling: Additional contraindications (not in US labeling): Severe bradyarrhythmia from second- or third-degree atrioventricular block or sick sinus syndrome; sinus node dysfunction; hereditary problems of galactose intolerance (eg, galactosemia).
Concerns related to adverse effects:
• CNS depression: May cause CNS depression (including sedation and somnolence), which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with severe coronary insufficiency, including recent MI. Epidural clonidine is not recommended for use in patients with severe cardiovascular disease or hemodynamic instability.
• 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.
Dosage form specific issues:
• Epidural use: Should be administered via continuous epidural infusion device.
• Product interchangeability: Oral formulations of clonidine (immediate release versus extended release) are not interchangeable on a mg:mg basis due to different pharmacokinetic profiles. Oral extended-release formulations of clonidine (Kapvay [indicated for attention-deficit/hyperactivity disorder in pediatric patients] vs Nexiclon XR [indicated for hypertension in adults]) 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 (discontinue oral immediate release or epidural dose gradually over 6 to 10 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.
Prior to treatment with medications for attention-deficit/hyperactivity disorder (ADHD), the American Heart Association and the American Academy of Pediatrics recommend that all children and adolescents diagnosed with ADHD have a thorough cardiovascular assessment, including patient and family health histories, determination of all medications used (prescribed and over-the-counter), and a physical examination focused on cardiovascular disease risk factors. An ECG is not mandatory but is reasonable to consider prior to stimulant medication therapy. Prompt evaluation and appropriate referral and testing, if warranted, should occur if any cardiac symptoms present (Vetter 2008). These recommendations are based upon reports of serious cardiovascular adverse events (including sudden death) in patients (both children and adults) taking usual doses of stimulant medications. Most of these patients were found to have underlying structural heart disease (eg, hypertrophic obstructive cardiomyopathy). ECG abnormalities and 4 cases of sudden cardiac death have been reported in children receiving clonidine with methylphenidate; a dose reduction of methylphenidate when used concurrently with clonidine has been suggested; consider ECG monitoring. In patients with ADHD, clonidine may cause hypotension and bradycardia; use with caution in patients with history of hypotension, heart block, bradycardia, cardiovascular disease, syncope, conditions predisposing to syncope (including orthostatic hypotension, dehydration), or receiving concomitant antihypertensive therapy. Patients should be advised to avoid becoming dehydrated or overheated. Heart rate and blood pressure should be monitored at initiation of therapy, with any dose increase, and periodically during therapy.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): May enhance the CNS depressant effect of CloNIDine. Alcohol (Ethyl) may increase the serum concentration of CloNIDine. Specifically, the rate of dissolution from the clonidine extended-release tablet may be enhanced in the presence of alcohol. Risk C: Monitor therapy
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: 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. Risk D: Consider therapy modification
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Risk C: Monitor therapy
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
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 at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: 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. Risk D: Consider therapy modification
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
EPHEDrine (Systemic): CloNIDine may enhance the therapeutic effect of EPHEDrine (Systemic). Risk C: Monitor therapy
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Fexinidazole: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole. Risk X: Avoid combination
Fingolimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Fingolimod. Management: Consult with the prescriber of any bradycardia-causing agent to see if the agent could be switched to an agent that does not cause bradycardia prior to initiating fingolimod. If combined, perform continuous ECG monitoring after the first fingolimod dose. Risk D: Consider therapy modification
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Herbal Products with Blood Pressure Increasing Effects: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Risk C: Monitor therapy
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Loop Diuretics: May enhance the hypotensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Macimorelin: CloNIDine may diminish the diagnostic effect of Macimorelin. Risk X: Avoid combination
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk D: Consider therapy modification
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: 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. Risk D: Consider therapy modification
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists 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. Risk D: Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
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. Risk D: Consider therapy modification
Ozanimod: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Ponesimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Ponesimod. Management: Avoid coadministration of ponesimod with drugs that may cause bradycardia when possible. If combined, monitor heart rate closely and consider obtaining a cardiology consult. Do not initiate ponesimod in patients on beta-blockers if HR is less than 55 bpm. Risk D: Consider therapy modification
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Serotonin/Norepinephrine Reuptake Inhibitors: May diminish the therapeutic effect of Alpha2-Agonists. Risk C: Monitor therapy
Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. If combined, consider obtaining a cardiology consult regarding patient monitoring. Risk D: 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. Risk D: Consider therapy modification
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Tricyclic Antidepressants: May diminish the antihypertensive effect of Alpha2-Agonists. Management: Consider avoiding this combination. If used, monitor for decreased effects of the alpha2-agonist. Exercise great caution if discontinuing an alpha2-agonist in a patient receiving a TCA. Risk D: Consider therapy modification
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: 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. Risk D: Consider therapy modification
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 due to an increase in nonrenal clearance, possibly regulated by maternal CYP2D6 genotype (Buchanan 2009; Claessens 2010).
Chronic maternal hypertension may increase the risk of birth defects, low birth weight, preterm delivery, stillbirth, and neonatal death. Actual fetal/neonatal risks may be related to duration and severity of maternal hypertension. Untreated hypertension may also increase the risks of adverse maternal outcomes, including gestational diabetes, myocardial infarction, preeclampsia, stroke, and delivery complications (ACOG 203 2019). Agents other than clonidine are more commonly used to treat hypertension in pregnancy (ACOG 203 2019; ESC [Regitz-Zagrosek 2018]); use of clonidine should be considered in consult with subspecialists (ACOG 203 2019). Females with preexisting hypertension may continue their medication during pregnancy unless contraindications exist (ESC [Regitz-Zagrosek 2018]).
If treatment for attention-deficit/hyperactivity disorder (ADHD) in pregnancy is needed, other agents are preferred (Ornoy 2018). Data collection to monitor pregnancy and infant outcomes following exposure to ADHD medications is ongoing. Health care providers are encouraged to enroll females exposed to Kapvay during pregnancy in the National Pregnancy Registry for ADHD Medications (866-961-2388).
[US Boxed Warning]: Epidural clonidine is not recommended for obstetrical or postpartum pain due to risk of hemodynamic instability. However, in a rare obstetrical, or postpartum patient, potential benefits may outweigh the possible risks. Severe maternal hypotension may occur following epidural use which may result in decreased placental perfusion. Clonidine has been evaluated for use as an adjunctive agent for epidural labor analgesia (Allen 2018; Kumari 2018; Landau 2002; Roelants 2015; Zhang 2015) including patients who are opioid dependent (Hoyt 2018).
Clonidine is present in breast milk.
Studies evaluating breast milk concentrations are limited (Boutroy 1988; Bunjes 1993; Hartikainen-Sorri 1987); concentrations may be up to 4 times those in maternal serum (Boutroy 1988). Based on available lactation studies, one manufacturer reports the relative infant dose of clonidine to be 4.1% to 8.4% of the weight adjusted maternal dose (maternal dose and milk concentrations presented).
Adverse events observed in some breastfed infants also exposed in utero include apathy syndrome, hypoglycemia, hypotonia, drowsiness, feeding difficulties, and hyperexcitability (Hartikainen-Sorri 1987; Sevrez 2014). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Other sources do not recommend use in breastfeeding women (Ornoy 2018) or recommend avoiding use when breastfeeding infants born <34 weeks' gestation or when large maternal doses are needed (Atkinson 1988). Infants exposed to clonidine via breast milk should be monitored for symptoms of hypotension and/or bradycardia (eg, sedation, lethargy, tachypnea, poor feeding).
Blood pressure, standing and sitting/supine, mental status, heart rate
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).
Hypertension: The 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults (ACC/AHA [Whelton 2018]):
Confirmed hypertension and known CVD or 10-year ASCVD risk ≥10%: Target blood pressure <130/80 mm Hg is recommended.
Confirmed hypertension without markers of increased CVD risk: Target blood pressure <130/80 mm Hg may be reasonable.
Stimulates alpha-2 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 alpha-2 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 alpha-2 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.
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; Transdermal: Steady state reached in ~3 days.
Attention-deficit/hyperactivity disorder: Oral: Extended release (Kapvay): Onset of action: 1 to 2 weeks (AAP [Wolraich 2011]).
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; 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.
Protein binding: 20% to 40%.
Metabolism: Extensively hepatic to inactive metabolites; undergoes enterohepatic recirculation.
Bioavailability: Oral: Immediate release: 70% to 80%; Extended release (Kapvay): ~89% (relative to immediate-release formulation); Transdermal: ~60%.
Half-life elimination:
Children: 6.13 ± 1.33 hours (Lonnqvist 1993).
Adults: Normal renal function: 12 to 16 hours; Renal impairment: ≤41 hours.
Epidural administration: CSF half-life elimination: 1.3 ± 0.5 hours; plasma half-life elimination: 22 ± 15 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]).
Time to peak, plasma: Oral: Immediate release: 1 to 3 hours; Extended release (Kapvay): 7 to 8 hours; Extended release (Nexiclon): 7.8 ± 1.7 hours.
Excretion: Urine (40% to 60% as unchanged drug).
Clearance:
Oral:
Neonates: 0.16 L/kg/hour (Xie 2011).
Infants and Children ≤4 years: ~0.3 L/kg/hour (Xie 2011).
Children 5 to 10 years: ~0.26 L/kg/hour (Xie 2011).
Adults: Single dose: ~0.25 L/kg/hour; Multiple dose: ~0.4 L/kg/hour (Frisk-Holmberg 1981).
Altered kidney function: The half-life increases up to 41 hours in patients with severe renal impairment.
Patch weekly (Catapres-TTS-1 Transdermal)
0.1 mg/24 hrs (per each): $87.07
Patch weekly (Catapres-TTS-2 Transdermal)
0.2 mg/24 hrs (per each): $146.61
Patch weekly (Catapres-TTS-3 Transdermal)
0.3 mg/24 hrs (per each): $203.38
Patch weekly (cloNIDine Transdermal)
0.1 mg/24 hrs (per each): $33.12 - $33.16
0.2 mg/24 hrs (per each): $55.77 - $55.83
0.3 mg/24 hrs (per each): $77.36 - $77.45
Solution (cloNIDine HCl (Analgesia) Epidural)
100 mcg/mL (per mL): $3.13 - $5.04
500 mcg/mL (per mL): $12.25 - $19.50
Solution (Duraclon Epidural)
100 mcg/mL (per mL): $5.28
Tablet, 12-hour (cloNIDine HCl ER Oral)
0.1 mg (per each): $4.50 - $7.95
Tablet, 12-hour (Kapvay Oral)
0.1 mg (per each): $2.23
Tablet, 24-hour (cloNIDine HCl ER Oral)
0.17 mg (per each): $19.74
Tablet, 24-hour (Nexiclon XR Oral)
0.17 mg (per each): $21.96
Tablets (cloNIDine HCl Oral)
0.1 mg (per each): $0.05 - $0.26
0.2 mg (per each): $0.08 - $0.45
0.3 mg (per each): $0.13 - $0.63
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