clonidine (Rx)

>10%

Skin reactions; patch (15-50%)

Dry mouth (40%)

Somnolence (19-38%)

Headache (19-29%)

Fatigue (13-24%)

Drowsiness (33%)

Dizziness (13-16%)

Hypotension, epidural (45%)

Postural hypotension, epidural (32%)

Anxiety (11%)

1-10%

Constipation (10%)

Sedation (10%)

Nausea/vomiting, PO (5%)

Malaise (3%)

Orthostatic hypotension (3%)

Anorexia, PO (1%)

Abnormal LFTs (1%)

Rash (1%)

Weight gain, PO (1%)

Frequency Not Defined

Children with ADHD

• Upper respiratory tract infection
• Irritability
• Throat pain
• Nightmares
• Insomnia
• Emotional disorder
• Constipation
• Nasal congestion

Postmarketing Reports

Hallucinations

AV block

Contraindications

Hypersensitivity

Epidural

• Concurrent anticoagulants, bleeding diathesis
• Presence of injection site infections
• Administration above C4 dermatome, due to lack of adequate safety data
• Obstetric/perioperative pain

Cautions

Epidural: Hemodynamically unstable patients (risk of severe hypotension)

Do not discontinue suddenly (risk of rebound hypertension)

Patch: May need to remove if severe erythema and/or localized vesicle formation develop at application site or generalized rash; consult physician

Severe coronary insufficiency

May cause xerostomia

Recent MI

Cerebrovascular disease

Chronic renal failure

Raynaud's disease

Thromboangiitis obliterans

History of depression (may exacerbate depression in cancer patients)

May impair ability to perform hazardous tasks

Remove patch before MRI (may cause burns)

Hypotension may occur; usually responsive to IV fluids and, if necessary, appropriate parenterally administered pressor agents

Cardiac conduction abnormalities: Sympatholytic action may worsen sinus node dysfunction and atrioventricular (AV) block, especially if coadministered with other sympatholytic drugs

Titrate slowly and monitor vital signs frequently in patients at risk for hypotension, heart block, bradycardia, syncope, cardiovascular disease, vascular disease, cerebrovascular disease or chronic renal failure; measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy; avoid concomitant use of drugs with additive effects unless clinically indicated; advise patients to avoid becoming dehydrated or overheated

Epidural administration may result in mild respiratory depression (usually with higher than recommended dose)

Use with caution in cerebrovascular disease

Avoid as first line antihypertensive in the elderly due to high risk for adverse side effects

Children may be particularly susceptible to hypertensive episodes when experiencing GI illnesses that lead to vomiting

Discontinue oral immediate release formulations within 4 hr of surgery; restart as soon as possible following surgery

Due to different pharmacokinetic profiles, oral formulations are not interchangeable with extended release on a mg-mg basis due to different pharmacokinetic profiles

Pregnancy

There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, during pregnancy; healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866- 961-2388 or visiting https://womensmentalhealth.org/adhd-medications

Prolonged experience with clonidine in pregnant women over several decades, based on published literature, including controlled trials, a retrospective cohort study and case reports, have not identified a drug associated risk of major birth defects, miscarriage, and adverse maternal or fetal outcomes

Based on findings in animal studies revealed that drug may impair fertility in females and males of reproductive potential

Animal data

• In animal embryofetal studies, increased resorptions were seen in rats and mice administered oral clonidine hydrochloride from implantation through organogenesis at 10 and 5 times, respectively, the maximum recommended human dose (MRHD) given to adolescents on a mg/m2 basis; no developmental effects were seen in rabbits administered drug during organogenesis at doses up to 3 times the MRHD

Lactation

Based on published lactation studies, clonidine hydrochloride is present in human milk at relative infant doses ranging from 4.1 to 8.4% of maternal weight-adjusted dosage; although in most cases, there were no reported adverse effects in breastfed infants exposed to clonidine, there is one case report of sedation, hypotonia, and apnea in an infant exposed to clonidine through breast milk; if an infant is exposed to clonidine hydrochloride through breastmilk, monitor for symptoms of hypotension and bradycardia, such as sedation, lethargy, tachypnea and poor feeding

Consider developmental and health benefits of breastfeeding along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from drug or from underlying maternal condition; exercise caution when drug is administered to a nursing woman

Monitor breastfeeding infants exposed to drug through breast milk for symptoms of hypotension and/or bradycardia such as sedation, lethargy, tachypnea, and poor feeding

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Central sympatholytic via stimulation of central alpha receptors; results in reduced sympathetic outflow, causing decreased PVR, HR, BP, and renal vascular resistance; produces presynaptic and postjunctional alpha-2 adrenoreceptor analgesia by preventing pain signal transmission to brain

Postsynaptic alpha2-agonist stimulation may regulate subcortical activity in the prefrontal cortex, which may regulate the area of the brain responsible for attention, emotions, and behaviors, and thereby reduces hyperactivity, distractibility, and impulsiveness

Absorption

Bioavailability: Immediate release (75-85%); extended release (89%)

Onset: <1 hr (2-4 hr peak effect in blood pressure)

Duration: 6-10 hr

Peak plasma time: 1-3 hr (immediate release); 7-8 hr (extended release)

Distribution

Protein bound: 20-40%

Vd: 2.9 L/kg

Metabolism

Liver

Elimination

Half-life: 12-16 hr

Excretion: Urine (40-60%)

Hypertension

Immediate release

• May administer with or without food
• The dose must be adjusted according to the patient’s individual blood pressure response
• Increments of 0.1 mg per day may be made at weekly intervals if necessary until desired response achieved; taking the larger portion of the oral daily dose at bedtime may minimize transient adjustment effects of dry mouth and drowsiness; therapeutic doses most commonly used have ranged from 0.2 mg to 0.6 mg per day given in divided doses; studies have indicated that 2.4 mg is maximum effective daily dose, but rarely used

Transdermal patch

• Apply the transdermal therapeutic system once every 7 days to a hairless area of intact skin on upper outer arm or chest; each new application of transdermal therapeutic system should be on a different skin site from previous location
• If the system loosens during 7-day wearing, the adhesive cover should be applied directly over system to ensure good adhesion; there have been rare reports of need for patch changes prior to 7 days to maintain blood pressure control
• To initiate therapy, titrate the transdermal therapeutic system dosage according to individual therapeutic requirements, starting with CATAPRES-TTS-1; if after one or two weeks the desired reduction in blood pressure not achieved, increase dosage by adding another CATAPRES-TTS-1 or changing to a larger system; an increase in dosage above two CATAPRES-TTS-3 is usually not associated with additional efficacy
• When substituting CATAPRES-TTS transdermal therapeutic system for oral clonidine or for other antihypertensive drugs, physicians should be aware that the antihypertensive effect of CATAPRES-TTS transdermal therapeutic system may not commence until 2-3 days after initial application; gradual reduction of prior drug dosage is advised; some or all previous antihypertensive treatment may have to be continued, particularly in patients with more severe forms of hypertension

Conversion of dosage forms

• Oral to transdermal

  • Day 1: Place Catapress-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 needed

• Transdermal to oral

  • Clonidine levels persist for 8 hr after removing transdermal patch and decrease slowly over several days; effects may persist for 24-48 hr after removal
  • Consider a persistent effect on blood pressure when initiating immediate release clonidine; consider initiating immediate release oral clonidine no sooner than 8 hr after patch removal

Attention Deficit Disorder

Extended-release tablets

• Substitution of extended-release for other clonidine products on an mg-per-mg basis not recommended
• Doses 0.2 mg/day or greater should be divided BID, with either an equal or higher split dosage being given at bedtime
• Tablet must be swallowed whole, never crushed, cut, or chewed, and may be taken with or without food; when initiating treatment, provide dosage escalation instructions

Cancer pain

• Dilute 500 mcg/mL to 100 mcg/mL with 0.9% NaCl before administration
• Epidural infusion considered as adjunct to intraspinal opiate therapy; epidural administration (Duraclon) is indicated in combination with opiates for the treatment of severe pain in patients with cancer not adequately relieved by opioid analgesics alone
• More likely to be effective in patients with neuropathic pain than in those with somatic or visceral pain