Pharmacodynamics

Hemodynamic studies in man showed that the decrease in blood pressure observed after single-dose or long-term oral treatment with guanfacine was accompanied by a significant decrease in peripheral resistance and a slight reduction in heart rate (5 beats/min). Cardiac output under conditions of rest or exercise was not altered by guanfacine.

Guanfacine lowered elevated plasma renin activity and plasma catecholamine levels in hypertensive patients, but this does not correlate with individual blood-pressure responses.

Growth hormone secretion was stimulated with single oral doses of 2 and 4 mg of guanfacine. Long-term use of guanfacine had no effect on growth hormone levels.

Guanfacine had no effect on plasma aldosterone. A slight but insignificant decrease in plasma volume occurred after one month of guanfacine therapy. There were no changes in mean body weight or electrolytes.

Pharmacokinetics

Relative to an intravenous dose of 3 mg, the absolute oral bioavailability of guanfacine is about 80%. Peak plasma concentrations occur from 1 to 4 hours with an average of 2.6 hours after single oral doses or at steady state.

The area under the concentration-time curve (AUC) increases linearly with the dose.

In individuals with normal renal function, the average elimination half-life is approximately 17 hr (range 10-30 hr). Younger patients tend to have shorter elimination half-lives (13-14 hr) while older patients tend to have half-lives at the upper end of the range. Steady state blood levels were attained within 4 days in most subjects.

In individuals with normal renal function, guanfacine and its metabolites are excreted primarily in the urine. Approximately 50% (40-75%) of the dose is eliminated in the urine as unchanged drug; the remainder is eliminated mostly as conjugates of metabolites produced by oxidative metabolism of the aromatic ring.

The guanfacine-to-creatinine clearance ratio is greater than 1, which would suggest that tubular secretion of drug occurs.

The drug is approximately 70% bound to plasma proteins, independent of drug concentration.

The whole body volume of distribution is high (a mean of 6.3 L/kg), which suggests a high distribution of drug to the tissues.

The clearance of guanfacine in patients with varying degrees of renal insufficiency is reduced, but plasma levels of drug are only slightly increased compared to patients with normal renal function. When prescribing for patients with renal impairment, the low end of the dosing range should be used. Patients on dialysis also can be given usual doses of guanfacine hydrochloride as the drug is poorly dialyzed.

General

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

Information for Patients

Patients who receive guanfacine should be advised to exercise caution when operating dangerous machinery or driving motor vehicles until it is determined that they do not become drowsy or dizzy from the medication. Patients should be warned that their tolerance for alcohol and other CNS depressants may be diminished. Patients should be advised not to discontinue therapy abruptly.

Laboratory Tests

In clinical trials, no clinically relevant laboratory test abnormalities were identified as causally related to drug during short-term treatment with guanfacine.

Drug Interactions

The potential for increased sedation when guanfacine is given with other CNS-depressant drugs should be appreciated.

The administration of guanfacine concomitantly with a known microsomal enzyme inducer (phenobarbital or phenytoin) to two patients with renal impairment reportedly resulted in significant reductions in elimination half-life and plasma concentration. In such cases, therefore, more frequent dosing may be required to achieve or maintain the desired hypotensive response. Further, if guanfacine is to be discontinued in such patients, careful tapering of the dosage may be necessary in order to avoid rebound phenomena (see Rebound above).

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenic effect was observed in studies of 78 weeks in mice at doses more than 150 times the maximum recommended human dose and 102 weeks in rats at doses more than 100 times the maximum recommended human dose. In a variety of test models, guanfacine was not mutagenic.

No adverse effects were observed in fertility studies in male and female rats.

Pregnancy Category B

Administration of guanfacine to rats at 70 times the maximum recommended human dose and to rabbits at 20 times the maximum recommended human dose resulted in no evidence of harm to the fetus. Higher doses (100 and 200 times the maximum recommended human dose in rabbits and rats respectively) were associated with reduced fetal survival and maternal toxicity. Rat experiments have shown that guanfacine crosses the placenta.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

Guanfacine is not recommended in the treatment of acute hypertension associated with toxemia of pregnancy. There is no information available on the effects of guanfacine on the course of labor and delivery.

Nursing Mothers

It is not known whether guanfacine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when guanfacine hydrochloride is administered to a nursing woman. Experiments with rats have shown that guanfacine is excreted in the milk.

Pediatric Use

Safety and effectiveness in pediatric patients under 12 years of age have not been demonstrated. Therefore, the use of guanfacine in this age group is not recommended. There have been spontaneous postmarketing reports of mania and aggressive behavioral changes in pediatric patients with attention-deficit hyperactivity disorder (ADHD) receiving guanfacine. The reported cases were from a single center. All patients had medical or family risk factors for bipolar disorder. All patients recovered upon discontinuation of guanfacine HCl. Hallunications have been reported in pediatric patients receiving guanfacine for treatment of attention-deficit hyperactivity disorder.

Geriatric Use

Clinical studies of guanfacine did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

Postmarketing Experience

An open-label postmarketing study involving 21,718 patients was conducted to assess the safety of guanfacine (as the hydrochloride) 1 mg/day given at bedtime for 28 days. Guanfacine was administered with or without other antihypertensive agents. Adverse events reported in the postmarketing study at an incidence greater than 1% included dry mouth, dizziness, somnolence, fatigue, headache, and nausea. The most commonly reported adverse events in this study were the same as those observed in controlled clinical trials.

Less frequent, possibly guanfacine-related events observed in the postmarketing study and/or reported spontaneously include:

BODY AS A WHOLE:                               asthenia, chest pain, edema, malaise, tremor

CARDIOVASCULAR:                               bradycardia, palpitations, syncope, tachycardia

CENTRAL NERVOUS SYSTEM: paresthesias, vertigo

EYE DISORDERS: blurred vision

GASTROINTESTINAL SYSTEM:            abdominal pain, constipation, diarrhea, dyspepsia

LIVER AND BILIARY SYSTEM:             abnormal liver function tests

MUSCULOSKELETAL SYSTEM:            arthralgia, leg cramps, leg pain, myalgia

PSYCHIATRIC:                        agitation, anxiety, confusion, depression, insomnia,

nervousness

REPRODUCTIVE SYSTEM, MALE: impotence

RESPIRATORY SYSTEM: dyspnea

SKIN AND APPENDAGES: alopecia, dermatitis, exfoliative dermatitis, pruritus,

rash

SPECIAL SENSES:                                      alterations in taste

URINARY SYSTEM:                                    nocturia, urinary frequency

Rare, serious disorders with no definitive cause and effect relationship to guanfacine have been reported spontaneously and/or in the postmarketing study. These events include acute renal failure, cardiac fibrillation, cerebrovascular accident, congestive heart failure, heart block, and myocardial infarction.

Signs and Symptoms:

Drowsiness, lethargy, bradycardia, and hypotension have been observed following overdose with guanfacine.

A 25-year-old female intentionally ingested 60 mg. She presented with severe drowsiness and bradycardia of 45 beats/minute. Gastric lavage was performed and an infusion of isoproterenol (0.8 mg in 12 hours) was administered. She recovered quickly and without sequelae.

A 28-year-old female who ingested 30-40 mg developed only lethargy, was treated with activated charcoal and a cathartic, was monitored for 24 hours, and was discharged in good health.

A 2-year-old male weighing 12 kg, who ingested up to 4 mg of guanfacine, developed lethargy. Gastric lavage (followed by activated charcoal and sorbitol slurry via NG tube) removed some tablet fragments within 2 hours after ingestion, and vital signs were normal.

During 24-hour observation in ICU, systolic pressure was 58 and heart rate 70 at 16 hours post-ingestion. No intervention was required, and child was discharged fully recovered the next day.