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Uses

Hypertension

Guanfacine hydrochloride is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.

Although other antihypertensive drug classes (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics) are preferred for the initial management of hypertension in adults, centrally acting agents such as guanfacine may be considered as add-on therapy if goal blood pressure cannot be achieved with the recommended drugs.

Hypotensive efficacy of guanfacine has been shown to be similar to that of clonidine and methyldopa.

Guanfacine has been used in conjunction with diuretics (e.g., thiazides), producing a greater reduction in blood pressure than is obtained with either drug alone. Use of a diuretic or other antihypertensive agents may aid in overcoming tolerance to guanfacine and permit reduction of guanfacine dosage.

For additional information on overall principles and expert recommendations for treatment of hypertension,

Attention Deficit Hyperactivity Disorder

Guanfacine hydrochloride has been used for the treatment of attention deficit hyperactivity disorder (ADHD) in pediatric patients. Guanfacine 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). Guanfacine may be especially useful in pediatric patients with comorbid tic disorders, which can be triggered or worsened by stimulant therapy. For a more detailed discussion on the management of ADHD,

Dosage and Administration

General

Hypertension

Dosage of guanfacine should be adjusted carefully according to the patient's blood pressure response and tolerance.

Blood pressure should be carefully monitored during initial guanfacine dosage titration or subsequent upward adjustment in dosage.

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure; specific target levels of blood pressure should be individualized based on consideration of multiple factors, including patient age and comorbidities, and the currently available evidence from clinical studies.

For additional information on initiating and adjusting guanfacine dosage in the management of hypertension,

Attention Deficit Hyperactivity Disorder

Blood pressure should be monitored, especially during initial dosage adjustment; some experts also recommend ECG monitoring.

Administration

Oral Administration

Adverse effects (e.g., somnolence) can be minimized by administering guanfacine initially at bedtime.

Dosage

Dosage of guanfacine hydrochloride is expressed in terms of guanfacine.

Pediatric Patients

Hypertension

For treatment of hypertension in children 12 years of age or older, the initial oral guanfacine dosage is 1 mg daily. If a satisfactory response is not obtained after 3-4 weeks of therapy, guanfacine dosage may be increased to 2 mg once daily at bedtime, although most of the antihypertensive effect is observed at a dosage of 1 mg daily.

Although higher dosages (i.e., exceeding 2 mg daily) have been used, oral dosages of guanfacine exceeding 3 mg daily were associated with a substantially increased incidence of adverse effects.

Attention Deficit Hyperactivity Disorder

For treatment of attention deficit hyperactivity disorder in children 7-14 years of age, an initial oral guanfacine dosage of 0.5 mg daily, given as a single dose at bedtime, has been used.

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

Adults

Hypertension

For treatment of hypertension in adults, the initial oral guanfacine dosage is 1 mg daily. If a satisfactory response is not obtained after 3-4 weeks of therapy, dosage may be increased to 2 mg once daily at bedtime, although most of the antihypertensive effect is observed at a dosage of 1 mg daily.

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

Some experts recommend a usual dosage range of 0.5-2 mg once daily.

Special Populations

Hepatic Impairment

There are no specific dosage recommendations at this time.

Renal Impairment

Guanfacine dosages at the low end of the dosing range should be administered in patients with renal impairment.

Usual doses of guanfacine (possibly at the low end of the dosing range) may be administered in patients undergoing dialysis, because limited amounts of the drug are removed by dialysis.

Geriatric Patients

Guanfacine dosage should be selected 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.

Cautions

Contraindications

Guanfacine is contraindicated in patients with known hypersensitivity to the drug.

Warnings/Precautions

Sensitivity Reactions

Rash

Rash with exfoliation has been reported in patients receiving guanfacine. Although a causal relationship to guanfacine has not been established, the drug should be discontinued if rash occurs and the patient be monitored appropriately.

General Precautions

Withdrawal Effects

There is a risk of symptoms of nervousness and anxiety and, less commonly, rebound hypertension, if guanfacine is stopped abruptly. Withdrawal effects occur less commonly than with clonidine; incidence may be about 3%.

Following abrupt discontinuance of guanfacine, blood pressure usually returns to pretreatment levels slowly (within 2-4 days) without ill effects. When rebound hypertension occurs, onset typically is 2-4 days after discontinuance of the drug (which is later than observed with discontinuance of clonidine hydrochloride).

Cardiovascular Effects

Like other antihypertensive agents, guanfacine should be used with caution in patients with severe coronary insufficiency, recent acute myocardial infarction, or cerebrovascular disease.

Nervous System Effects

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

Specific Populations

Pregnancy

Category B.

Guanfacine is not recommended for the treatment of acute hypertension associated with toxemia of pregnancy.

Lactation

Guanfacine is distributed into milk in rats; it is not known whether the drug is distributed into human milk. Caution is advised if guanfacine is used in nursing women.

Pediatric Use

Safety and efficacy of guanfacine for the management of hypertension have not been established in children younger than 12 years of age; use in these pediatric patients is not recommended. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients,

Safe use for the management of attention deficit hyperactivity disorder (ADHD) in children has not been established, but clinical studies currently are under way to determine safety and efficacy. Mania and aggressive behavioral changes have been reported in pediatric patients with ADHD receiving the drug; all patients had medical or family risk factors for bipolar disorder. All patients recovered following discontinuance of the drug.

Geriatric Use

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

Dosage of guanfacine should be selected with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

Hepatic Impairment

Like other antihypertensive agents, guanfacine should be used with caution in patients with chronic hepatic failure.

Renal Impairment

Like other antihypertensive agents, guanfacine should be used with caution in patients with chronic renal failure.

Common Adverse Effects

Common adverse effects in patients receiving guanfacine include dry mouth, somnolence, dizziness, constipation, fatigue, asthenia, impotence, and headache.

Drug Interactions

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. More frequent dosing of guanfacine may be required in patients receiving such concomitant therapy.(See Phenobarbitalandsee Phenytoin under Drug Interactions.)Dosage of guanfacine should be tapered when the drug is to be discontinued in patients receiving microsomal enzyme inducers; such tapering therefore may avoid rebound hypertension or other symptoms.

Anticoagulants

Pharmacokinetic interaction with guanfacine is unlikely.

Antigout Drugs

Pharmacokinetic interaction with guanfacine is unlikely.

Antilipemic Agents

Pharmacokinetic interaction with guanfacine is unlikely.

β-Adrenergic Blocking Agents

Pharmacokinetic interaction with guanfacine is unlikely.

Bronchodilators

Pharmacokinetic interaction with guanfacine is unlikely.

Cardiac Drugs

Pharmacokinetic interaction between guanfacine and cardiac glycosides or coronary vasodilators is unlikely.

CNS Depressants

Concomitant use of guanfacine with barbiturates, benzodiazepines, or phenothiazines may potentiate CNS depression; caution should be used during concomitant administration of these drugs with guanfacine.

Contraceptives, Oral

Pharmacokinetic interaction with guanfacine is unlikely.

Cough and Cold Preparations

Pharmacokinetic interaction with guanfacine is unlikely.

Diuretics

There is an additive or potentiated hypotensive effect when guanfacine is used concomitantly with diuretics. Pharmacokinetic interaction with guanfacine is unlikely.

Hypoglycemic Agents

Pharmacokinetic interaction between guanfacine and oral hypoglycemic agents or insulin is unlikely.

Nonsteroidal Anti-inflammatory Agents

Pharmacokinetic interaction with guanfacine is unlikely.

Phenobarbital

There is a decreased elimination half-life and plasma concentration of guanfacine in patients with renal failure when the drug is used concomitantly with phenobarbital; a withdrawal reaction may occur. In patients receiving phenobarbital, dosage of guanfacine should be tapered carefully when the drug is to be discontinued.

Phenytoin

In patients with renal failure receiving guanfacine concomitantly with phenytoin, elimination half-life and plasma concentration of guanfacine may be decreased; a withdrawal reaction may occur. In patients receiving phenytoin, dosage of guanfacine should be tapered carefully when the drug is to be discontinued.

Pharmacokinetics

Absorption

Bioavailability

The absolute oral bioavailability of guanfacine is about 80%. Peak plasma guanfacine concentrations usually are attained within 1-4 hours (average: 2.6 hours).

Duration

Blood pressure response persists up to 24 hours following a single oral dose.

Distribution

Extent

Guanfacine is extensively distributed to tissues. Highest guanfacine concentrations are found in highly perfused organs (e.g., kidney, liver); lower concentrations are found in the brain, testis, and plasma.

Guanfacine crosses the placenta in rats; it is not known whether the drug crosses the placenta in humans.

Guanfacine is distributed into milk in rats; it is not known whether the drug is distributed into human milk.

Plasma Protein Binding

Plasma protein binding of guanfacine is approximately 70%.

Elimination

Metabolism

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

Elimination Route

It appears that guanfacine is excreted by tubular secretion.

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

Half-life

In patients with normal renal function, guanfacine half-life is about 17 hours (range: 10-30 hours).

Special Populations

Clearance of guanfacine is reduced in patients with renal impairment; however, plasma concentrations of the drug are only slightly increased.

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