Guanfacine

Class: Central alpha-Agonists
VA Class: CV490
Chemical Name: N-Amidino-2-(2,6-dichlorophenyl) acetamide monohydrochloride
Molecular Formula: C₉H₉Cl₂N₃O
CAS Number: 29110-47-2
Brands: Tenex

Introduction

Phenylacetyl-guanidine derivative hypotensive agent; selective α₂-adrenergic agonist.^{1 2}

Uses for Guanfacine

Hypertension

Used alone or in combination with other classes of antihypertensive agents in the management of hypertension.^{1 3 4 5 6 8}

Thiazide diuretics are considered the preferred initial monotherapy for uncomplicated hypertension by JNC 7.^{6 7 8}

Hypotensive efficacy shown to be similar to that of clonidine and methyldopa.^{2 3 4}

Has been used in conjunction with diuretics (e.g., thiazides), producing a greater reduction in BP than is obtained with either drug alone.^{1 5 16}

Use of a diuretic or other antihypertensive agents may aid in overcoming tolerance to guanfacine and permit reduction of guanfacine dosage.²

Attention Deficit Hyperactivity Disorder

Has been used for the treatment of attention deficit hyperactivity disorder† (ADHD) in pediatric patients.^{9 10}

Produces a moderate reduction in symptoms of ADHD†; stimulants (e.g., methylphenidate, amphetamines) remain the drugs of choice for the management of ADHD because of their greater efficacy compared with that of other drugs (e.g., guanfacine).⁹

May be especially useful in pediatric patients with comorbid tic disorders, which can be triggered or worsened by stimulant therapy.⁹

Guanfacine Dosage and Administration

General

Hypertension

• 
  

  Adjust dosage carefully according to patient’s BP response and tolerance.^{1 2}

  
  


• 
  

  Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.⁶

  
  


• 
  

  Avoid large or abrupt reductions in BP.¹¹

  
  


• 
  

  Adjust dosage at approximately monthly intervals (more aggressively in high-risk patients [stage 2 hypertension, comorbid conditions]) if BP control is inadequate at a given dosage; it may take months to control hypertension adequately while avoiding adverse effects of therapy.^{6 11}

  
  


• 
  

  SBP is the principal clinical end point, especially in middle-aged and geriatric patients.^{6 12 13} Once the goal SBP is attained, the goal DBP usually is achieved.⁶

  
  


• 
  

  The goal is to achieve and maintain a lifelong SBP <140 mm Hg and a DBP <90 mm Hg if tolerated.^{6 11 14}

  
  


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  The goal in hypertensive patients with diabetes mellitus or renal impairment is to achieve and maintain an SBP <130 mm Hg and a DBP <80 mm Hg.^{6 11 14 15}

  
  

Attention Deficit Hyperactivity Disorder

• 
  

  Monitor BP, especially during initial dosage adjustment;⁹ some experts also recommend ECG monitoring.¹⁰

  
  

Administration

Oral Administration

Minimize adverse effects (e.g., somnolence) by administering guanfacine initially at bedtime.¹

Dosage

Available as guanfacine hydrochloride; dosage expressed in terms of guanfacine.¹

Pediatric Patients

Hypertension

Oral

Children ≥12 years of age: Initially, 1 mg daily.¹

If a satisfactory response is not obtained after 3–4 weeks of therapy, may increase dosage to 2 mg once daily at bedtime, although most of the antihypertensive effect is observed at a dosage of 1 mg daily.^{1 5}

Although higher dosages (i.e., >2 mg daily) have been used, dosages >3 mg daily were associated with a substantially increased incidence of adverse effects.^{1 2}

Attention Deficit Hyperactivity Disorder†

Oral

Children 7–14 years of age: Initially, 0.5 mg daily (given as a single dose at bedtime) has been administered.⁹

Dosage has been increased with caution over 2–4 weeks (e.g., by 0.5 mg every 4 days) to a maximum of 4 mg daily in 3 divided doses.⁹

Adults

Hypertension

Oral

Initially, 1 mg daily.¹

If a satisfactory response is not obtained after 3–4 weeks of therapy, may increase dosage to 2 mg once daily at bedtime, although most of the antihypertensive effect is observed at a dosage of 1 mg daily.^{1 5}

Although higher dosages (i.e., >2 mg daily) have been used, dosages >3 mg daily were associated with a substantially increased incidence of adverse effects.^{1 2}

Prescribing Limits

Pediatric Patients

Hypertension

Oral

Children ≥12 years of age: Dosages >3 mg daily were associated with a substantially increased incidence of adverse effects.^{1 2 5}

Attention Deficit Hyperactivity Disorder†

Oral

Children 7–14 years of age: Maximum 4 mg daily.^{9 10 16}

Adults

Hypertension

Oral

Dosages >3 mg daily were associated with a substantially increased incidence of adverse effects.^{1 2 5}

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.¹

Renal Impairment

Administer dosages at the low end of the dosing range in patients with renal impairment.^{1 16 16}

May administer usual doses (possibly at low end of dosing range) in patients undergoing dialysis, because limited amounts of the drug are removed by dialysis.¹

Geriatric Patients

Select dosage with caution (usually starting at the low end of the dosing range) because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Cautions for Guanfacine

Contraindications

• 
  

  Known hypersensitivity to the drug.¹

  
  

Warnings/Precautions

Sensitivity Reactions

Rash

Skin rash with exfoliation reported.¹ Although causal relationship to guanfacine not established, discontinue drug if rash occurs and appropriately monitor patient.¹

General Precautions

Withdrawal Effects

Risk of symptoms of nervousness and anxiety and, less commonly, rebound hypertension, if drug is stopped abruptly.¹ Occurs less commonly than with clonidine;^{1 2 3} incidence may be about 3%.²

Following abrupt discontinuance of guanfacine, BP usually returns to pretreatment levels slowly (within 2–4 days) without ill effects.^{1 3} When rebound hypertension occurs, onset typically is 2–4 days after discontinuance of the drug (which is later than observed with clonidine hydrochloride).¹

Cardiovascular Effects

Like other antihypertensive agents, use with caution in patients with severe coronary insufficiency, recent AMI, or cerebrovascular disease.¹

Nervous System Effects

Risk of dose-related sedation/drowsiness, especially during initial therapy.¹ Performance of activities requiring mental alertness and physical coordination (operating machinery, driving a motor vehicle) may be impaired.¹

Specific Populations

Pregnancy

Category B.¹

Not recommended for the treatment of acute hypertension associated with toxemia of pregnancy.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Use caution.¹

Pediatric Use

Safety and efficacy for management of hypertension not established in children <12 years of age; use not recommended.¹

Safe use for the management of ADHD in children has not been established, but clinical studies currently are under way to determine safety and efficacy.^{9 10}

Mania and aggressive behavioral changes reported in pediatric patients with ADHD receiving the drug;¹ all patients had medical or family risk factors for bipolar disorder.¹ All patients recovered following discontinuance of the drug.¹

Geriatric Use

Clinical trial data for patients ≥65 years of age insufficient to determine whether geriatric patients respond differently than younger adults. ¹ Other experience suggests that response is similar to that in younger adults.¹

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.¹

Hepatic Impairment

Like other antihypertensive agents, use guanfacine with caution in patients with chronic hepatic failure.¹

Renal Impairment

Like other antihypertensive agents, use with caution in patients with chronic renal failure.¹

Common Adverse Effects

Dry mouth,^{1 4 5} somnolence,^{1 3 4 5} dizziness,^{1 4 5} constipation,¹ fatigue,^{1 4 5} asthenia,^{1 5} impotence,^{1 4 5} headache.^{1 4 5}

Interactions for Guanfacine

Drugs Affecting Hepatic Microsomal Enzymes

In a limited number of patients with renal impairment, concomitant administration of guanfacine with a known microsomal enzyme inducer (phenobarbital or phenytoin) resulted in decreased elimination half-life and plasma concentrations of guanfacine.¹ More frequent dosing of guanfacine may be required in patients receiving such concomitant therapy.¹ (See Specific Drugs under Interactions.) Taper dosage of guanfacine when the drug is to be discontinued in patients receiving microsomal enzyme inducers; may avoid rebound hypertension or other symptoms.¹

Specific Drugs

Drug	Interaction	Comments
Anticoagulants	Pharmacokinetic interaction unlikely1
Antigout drugs	Pharmacokinetic interaction unlikely1
Antilipemic agents	Pharmacokinetic interaction unlikely1
β-Adrenergic blocking agents	Pharmacokinetic interaction unlikely1
Bronchodilators	Pharmacokinetic interaction unlikely1
Cardiac drugs (glycosides, coronary vasodilators)	Pharmacokinetic interaction unlikely1
CNS depressants (barbiturates, benzodiazepines, phenothiazines)	May potentiate CNS depression1	Use concomitantly with caution1
Contraceptives (oral)	Pharmacokinetic interaction unlikely1
Cough and cold preparations	Pharmacokinetic interaction unlikely1
Diuretics	Additive/potentiated hypotensive effect1 Pharmacokinetic interaction unlikely1	Usually used to therapeutic advantage in antihypertensive therapy1
Hypoglycemic agents (oral or insulin)	Pharmacokinetic interaction unlikely1
NSAIAs	Pharmacokinetic interaction unlikely1
Phenobarbital	Decreased elimination half-life and plasma concentration of guanfacine in patients with renal failure; 1 withdrawal reaction may occur1 2	In patients receiving phenobarbital, carefully taper guanfacine dosage when drug is to be discontinued1
Phenytoin	Decreased elimination half-life and plasma concentration of guanfacine in patients with renal failure; 1 withdrawal reaction may occur1	In patients receiving phenytoin, carefully taper guanfacine dosage when drug is to be discontinued 1

Guanfacine Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability is about 80%.¹ Peak plasma concentrations usually attained within 1–4 hours (average: 2.6 hours).¹

Duration

BP response persists ≤24 hours following single oral dose.¹

Distribution

Extent

Extensively distributed to tissues.^{1 2} Highest concentrations in highly perfused organs (e.g., kidney, liver); lower concentrations in the brain, testis, and plasma.²

Crosses the placenta in rats; not known whether crosses placenta in humans.¹

Distributed into milk in rats; not known whether distributed into human milk.¹

Plasma Protein Binding

Approximately 70%.¹

Elimination

Metabolism

Approximately 50–70% of a dose is metabolized rapidly in the liver,^{1 2} mainly by oxidative metabolism of the aromatic ring to form the inactive 3-hydroxy derivative (major metabolite),^{1 2} which undergoes conjugation.²

Elimination Route

It appears that the drug is excreted by tubular secretion.¹

In patients with normal renal function, eliminated principally in the urine as unchanged drug (about 50%; range: 40–75%),¹ with remainder eliminated mostly as glucuronide (30–40%) or sulfate (8%).²

Half-life

In patients with normal renal function: about 17 hours (range: 10–30 hours).^{1 2}

Special Populations

Clearance reduced in patients with renal impairment; however, plasma concentrations of drug only slightly increased.¹

Within the reported range of elimination half-lives (10–30 hours), elimination half-life tends to be shorter (13–14 hours) in younger patients and longer (in the upper end of the range) in older patients.¹

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 15–30°C.¹

ActionsActions

• 
  

  Appears to stimulate α₂-adrenergic receptors in the CNS, causing inhibition of sympathetic vasomotor centers.^{1 2} Contributes predominantly to hypotensive effects.^{1 2}

  
  


• 
  

  Central effects result in reduced peripheral sympathetic nerve impulses from the vasomotor center to the heart and blood vessels, resulting in a decrease in peripheral vascular resistance and a reduction in heart rate.¹

  
  


• 
  

  Under conditions of rest or exercise, cardiac output is not altered.¹

  
  


• 
  

  Reduces BP in both supine and standing positions;¹ hypotensive effects may be somewhat greater in the standing position.²

  
  


• 
  

  Peripheral effects (stimulation of peripheral α₂-adrenergic receptors) also may contribute to hypotensive effects.²

  
  


• 
  

  Lowers elevated plasma renin activity and plasma catecholamine concentrations in patients with hypertension, although these effects do not correlate with individual hypotensive responses.^{1 2}

  
  


• 
  

  Acute administration stimulates release of growth hormone, but the drug does not produce sustained elevation of growth hormone during chronic administration.^{1 2}

  
  


• 
  

  Does not affect plasma aldosterone, mean body weight, or electrolytes; slight but insignificant increase in plasma volume observed after 1 month of therapy.¹

  
  


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  Reduces serum prolactin concentrations in hypertensive patients with elevated serum prolactin concentrations.²

  
  


• 
  

  Enhances neurologic activity in the prefrontal cortex, an area of the brain involved in planning, impulse control, and organization.¹⁰ Shown in nonhuman primates to improve prefrontal cortical function through direct action on postsynaptic α_2A-adrenergic receptors located in the prefrontal cortex.⁹

  
  


• 
  

  Sedative effects, which are less severe than those seen with clonidine,^{3 9} are the result of inhibitory effects on noradrenergic locus ceruleus neurons and direct effects on the thalamus.⁹

  
  

Advice to Patients

• 
  

  Importance of advising patients not to discontinue therapy abruptly because of the risk of withdrawal symptoms (e.g., nervousness, anxiety) and, less commonly, rebound hypertension.¹ (See Withdrawal Effects under Cautions.)

  
  


• 
  

  Importance of advising patients to exercise caution when operating dangerous machinery or driving motor vehicles until it is known that the drug is not causing untoward dizziness or drowsiness.¹

  
  


• 
  

  Importance of advising patients of the potential for decreased tolerance for alcohol and other CNS depressants.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Guanfacine Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	1 mg (of guanfacine)*	Guanfacine Hydrochloride Tablets
			Tenex	Reddy
		2 mg (of guanfacine)*	Guanfacine Hydrochloride Tablets
			Tenex	Reddy

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 04/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Guanfacine HCl 1MG Tablets (MYLAN): 30/$20.99 or 90/$60.99

Guanfacine HCl 2MG Tablets (MYLAN): 30/$25.99 or 90/$75.99

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 01, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Watson Laboratories, Inc. Guanfacine hydrochloride tablets prescribing information. Corona, CA; 2003 Apr.

2. Cornish LA. Guanfacine hydrochloride: a centrally acting antihypertensive agent. Clin Pharm. 1988; 7:187-97. [PubMed 3281788]

3. Wilson MF, Haring G, Lewin A et al. Comparison of guanfacine versus clonidine for efficacy, safety, and occurrence of withdrawal syndrome in step-2 treatment of mild to moderate essential hypertension. Am J Cardiol. 1986; 57:E43-49.

4. Wilson MF, Blackshear J, Parsons OA et al. Antihypertensive efficacy of guanfacine and methyldopa in patients with mild to moderate essential hypertension. J Clin Pharmacol. 1991; 31:318-26. [PubMed 2037703]

5. Materson BJ, Kessler WB, Alderman MH et al. A multicenter, randomized, double-blind dose-response evaluation of step-2 guanfacine versus placebo in mild to moderate hypertension. Am J Cardiol. 1986; 57:E32-37.

6. National Heart, Lung, and Blood Institute National High BP Education Program. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP (JNC VII) Express. Bethesda, MD: May 14 2003. From NIH website. (Also published in JAMA. 2003; 289:2560-72.

7. The Guidelines Subcommittee of the WHO/ISH Mild Hypertension Liaison Committee. 1999 guidelines for the management of hypertension. J Hypertension. 1999; 17:392-403.

8. National Heart, Lung, and Blood Institute National High BP Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP (JNC 7) Complete Version. Bethesda, MD: 2003 Nov 5. Hypertension. 2003; 42:1206-52. [PubMed 14656957]

9. Scahill L, Chappell PB, Kim YS et al. A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Am J Psychiatry. 2001; 158:1067-74. [PubMed 11431228]

10. Yan J. Nonstimulant ADHD medication moves closer to FDA approval. Psychiatr News. 2007; 42:18.

11. National Heart, Lung, and Blood Institute National High BP Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP (JNC VI). Bethesda, MD: National Institutes of Health; 1997 Nov. (NIH publication No. 98-4080.)

12. Izzo JL, Levy D, Black HR. Importance of systolic BP in older Americans. Hypertension. 2000; 35:1021-4. [PubMed 10818056]

13. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension. 2000; 35:1019-20. [PubMed 10818055]

14. Guidelines Committee. 2003 European Society of Hypertension–European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertension. 2003; 21:1011-53.

15. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care. 2003; 26(Suppl 1):S80-2. [PubMed 12502624]

16. Reviewers’ comments (personal observations.)

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