ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Adverse reactions noted with guanfacine are similar to those of other drugs of the central adrenoreceptor agonist class: dry mouth, sedation (somnolence), weakness (asthenia), dizziness, constipation, and impotence. While the reactions are common, most are mild and tend to disappear on continued dosing. Skin rash with exfoliation has been reported in few cases; although clear cause and effect relationships to guanfacine could not be established, should rash occur, guanfacine should be discontinued and the patient monitored appropriately.In the dose-response monotherapy study described under CLINICAL PHARMACOLOGY, the frequency of the most commonly observed adverse reactions showed dose relationship from 0.5 to mg as follows: Adverse ReactionPlacebon=590.5 mgn=601 mgn=612 mgn=603 mgn=59 Dry Mouth0%10%10%42%54% Somnolence8%5%10%13%39% Asthenia0%2%3%7%3% Dizziness8%12%2%8%15% Headache8%13%7%5%3% Impotence0%0%0%7%3% Constipation0%2%0%5%15% Fatigue2%2%5%8%10%The percent of patients who dropped out because of adverse reactions are shown below for each dosage group.Placebo0.5 mg1 mg2 mg3 mg Percent dropouts0%2%5%13%32%The most common reasons for dropouts among patients who received guanfacine were dry mouth, somnolence, dizziness, fatigue, weakness, and constipation.In the 12-week placebo-controlled, dose-response study of guanfacine administered with 25 mg chlorthalidone at bedtime, the frequency of the most commonly observed adverse reactions showed clear dose relationship from 0.5 to mg as follows:Adverse ReactionPlacebon 730.5 mgn 721 mgn 722 mgn 723 mgn 72 Dry mouth5 (7%)4 (5%)6 (8%)8 (11%)20 (28%) Somnolence1 (1%)3 (4%)0 (0%)1 (1%)10 (14%) Asthenia0 (0%)2 (3%)0 (0%)2 (2%)7 (10%) Dizziness2 (2%)1 (1%)3 (4%)6 (8%)3 (4%) Headache3 (4%)4 (3%)3 (4%)1 (1%)2 (2%) Impotence1 (1%)1 (0%)0 (0%)1 (1%)3 (4%) Constipation0 (0%)0 (0%)0 (0%)1 (1%)1 (1%) Fatigue3 (3%)2 (3%)2 (3%)5 (6%)3 (4%)There were 41 premature terminations because of adverse reactions in this study. The percent of patients who dropped out and the dose at which the dropout occurred were as follows: Dose: Placebo0.5 mg1 mg2 mg3 mg Percent dropouts6.9%4.2%3.2%6.9%8.3%Reasons for dropouts among patients who received guanfacine were: somnolence, headache, weakness, dry mouth, dizziness, impotence, insomnia, constipation, syncope, urinary incontinence, conjunctivitis, paresthesia, and dermatitis.In second 12-week placebo-controlled combination therapy study in which the dose could be adjusted upward to mg per day in 1-mg increments at 3-week intervals, i.e., setting more similar to ordinary clinical use, the most commonly recorded reactions were: dry mouth, 47%; constipation, 16%; fatigue, 12%; somnolence, 10%; asthenia, 6%; dizziness, 6%; headache, 4%; and insomnia, 4%.Reasons for dropouts among patients who received guanfacine were: somnolence, dry mouth, dizziness, impotence, constipation, confusion, depression, and palpitations.In the clonidine/guanfacine comparison described in CLINICAL PHARMACOLOGY, the most common adverse reactions noted were as follows: Adverse ReactionsGuanfacine(n=279)Clonidine(n=278) Dry Mouth30%37% Somnolence21%35% Dizziness11%8% Constipation10%5% Fatigue9%8% Headache4%4% Insomnia4%3%Adverse reactions occurring in 3% or less of patients in the three controlled trials of guanfacine with diuretic were:Cardiovascular bradycardia, palpitations, substernal painGastrointestinal abdominal pain, diarrhea, dyspepsia, dysphagia, nauseaCNS amnesia, confusion, depression, insomnia, libido decreaseENT disorders rhinitis, taste perversion, tinnitusEye disorders conjunctivitis, iritis, vision disturbanceMusculoskeletal leg cramps, hypokinesiaRespiratory dyspneaDermatologic dermatitis, pruritus, purpura, sweatingUrogenital testicular disorder, urinary incontinenceOther malaise, paresthesia, paresisAdverse reaction reports tend to decrease over time. In an open-label trial of one years duration, 580 hypertensive subjects were given guanfacine, titrated to achieve goal blood pressure, alone (51%), with diuretic (38%), with beta blocker (3%), with diuretic plus beta blocker (6%), or with diuretic plus vasodilator (2%). The mean daily dose of guanfacine reached was 4.7 mg.Adverse ReactionIncidence of adverse reactions at any time during the studyn=580Incidence of adverse reactions at end of one yearn=580Dry Mouth60%15%Drowsiness33%6%Dizziness15%1%Constipation14%3%Weakness5%1%Headache4%0.2%Insomnia5%0%There were 52 (8.9%) dropouts due to adverse effects in this 1-year trial. The causes were: dry mouth (n=20), weakness (n=12), constipation (n=7), somnolence (n=3), nausea (n=3), orthostatic hypotension (n=2), insomnia (n=1), rash (n=1), nightmares (n=1), headache (n=1), and depression (n=1).. Postmarketing Experience. An open-label postmarketing study involving 21,718 patients was conducted to assess the safety of guanfacine (as the hydrochloride) 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 WHOLE: asthenia, chest pain, edema, malaise, tremorCARDIOVASCULAR: bradycardia, palpitations, syncope, tachycardiaCENTRAL NERVOUS SYSTEM: paresthesias, vertigoEYE DISORDERS: blurred visionGASTROINTESTINAL SYSTEM: abdominal pain, constipation, diarrhea, dyspepsiaLIVER AND BILIARY SYSTEM: abnormal liver function testsMUSCULOSKELETAL SYSTEM: arthralgia, leg cramps, leg pain, myalgiaPSYCHIATRIC: agitation, anxiety, confusion, depression, insomnia, nervousnessREPRODUCTIVE SYSTEM, MALE: impotenceRESPIRATORY SYSTEM: dyspneaSKIN AND APPENDAGES: alopecia, dermatitis, exfoliative dermatitis, pruritus, rashSPECIAL SENSES: alterations in tasteURINARY SYSTEM: nocturia, urinary frequencyRare, 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 variety of test models, guanfacine was not mutagenic.No adverse effects were observed in fertility studies in male and female rats.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Guanfacine hydrochloride is an orally active antihypertensive agent whose principal mechanism of action appears to be stimulation of central 2-adrenergic receptors. By stimulating these receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in decrease in peripheral vascular resistance and reduction in heart rate. The dose-response relationship for blood pressure and adverse effects of guanfacine given once day as monotherapy has been evaluated in patients with mild to moderate hypertension. In this study patients were randomized to placebo or to 0.5 mg, mg, mg, mg, or mg of guanfacine. Results are shown in the following table. useful effect was not observed overall until doses of mg were reached, although responses in white patients were seen at mg; 24 hour effectiveness of mg to mg doses was documented using 24 hour ambulatory monitoring. While the mg dose added an increment of effectiveness, it caused an unacceptable increase in adverse reactions.Mean Changes (mm Hg) from Baseline in Seated Systolic and Diastolic Blood Pressure for Patients Completing to Weeks of Treatment with Guanfacine MonotherapyMean Change S/D Seatedn= (range)Placebo0.5 mg1 mg2 mg3 mg5 mgWhite Patients11-30-1/-5-6/-8-8/-9-12/-11-15/-12-18/-16Black Patients8-28-3/-50/-2-3/-5-7/-7-8/-9-19/-15S/D=Systolic/diastolic blood pressureControlled clinical trials in patients with mild to moderate hypertension who were receiving thiazide-type diuretic have defined the dose-response relationship for blood pressure response and adverse reactions of guanfacine given at bedtime and have shown that the blood pressure response to guanfacine can persist for 24 hours after single dose. In the 12-week placebo-controlled dose-response study, patients were randomized to placebo or to doses of 0.5, 1, 2, and mg of guanfacine, in addition to 25 mg chlorthalidone, each given at bedtime. The observed mean changes from baseline, tabulated below, indicate the similarity of response for placebo and the 0.5 mg dose. Doses of 1, 2, and mg resulted in decreased blood pressure in the sitting position with no real differences among the three doses. In the standing position there was some increase in response with dose.Mean Decreases (mm Hg) in Seated and Standing Blood Pressure for Patients Treated with Guanfacine in Combination with ChlorthalidoneMean Changen=Placebo 630.5 mg 631 mg 642 mg 583 mg 59S/D Seated-5/-7-5/-6-14/-13-12/-13-16/-13S/D Standing-3/-5-5/-4-11/-9-9/-10-15/-12S/D Systolic/diastolic blood pressureWhile most of the effectiveness of guanfacine in combination (and as monotherapy in white patients) was present at mg, adverse reactions at this dose were not clearly distinguishable from those associated with placebo. Adverse reactions were clearly present at and mg (see ADVERSE REACTIONS). In second 12-week placebo-controlled study 1, 2, or mg of guanfacine hydrochloride administered with 25 mg chlorthalidone once daily, significant decrease in blood pressure was maintained for full 24 hours after dosing. While there was no significant difference between the 12 and 24 hour blood pressure readings, the fall in blood pressure at 24 hours was numerically smaller, suggesting possible escape of blood pressure in some patients and the need for individualization of therapy.In double-blind, randomized trial, either guanfacine or clonidine was given at recommended doses with 25 mg chlorthalidone for 24 weeks and then abruptly discontinued. Results showed equal degrees of blood pressure reduction with the two drugs and there was no tendency for blood pressures to increase despite maintenance of the same daily dose of the two drugs. Signs and symptoms of rebound phenomena were infrequent upon discontinuation of either drug. Abrupt withdrawal of clonidine produced rapid return of diastolic and especially, systolic blood pressure to approximately pretreatment levels, with occasional values significantly greater than baseline, whereas guanfacine withdrawal produced more gradual increase to pretreatment levels, but also with occasional values significantly greater than baseline.. 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 significant decrease in peripheral resistance and 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 and mg of guanfacine. Long-term use of guanfacine had no effect on growth hormone levels.Guanfacine had no effect on plasma aldosterone. 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 mg, the absolute oral bioavailability of guanfacine is about 80%. Peak plasma concentrations occur from to 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 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 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.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Guanfacine hydrochloride tablets are contraindicated in patients with known hypersensitivity to guanfacine hydrochloride.

DESCRIPTION SECTION.

DESCRIPTION. Guanfacine hydrochloride is centrally acting antihypertensive with 2-adrenoceptor agonist properties in tablet form for oral administration. The chemical name of guanfacine hydrochloride is N-Amidino-2-(2,6-dichlorophenyl) acetamide monohydrochloride and its molecular weight is 282.55. Its structural formula is:Guanfacine hydrochloride is white to off-white powder; sparingly soluble in water and alcohol and slightly soluble in acetone.Each tablet, for oral administration, contains guanfacine hydrochloride equivalent to mg or mg guanfacine. The tablets contain the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, partially pregelatinized starch, magnesium stearate and talc. The mg tablet also contains D&C Yellow 10 Aluminum Lake.. Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. The recommended initial dose of guanfacine (as the hydrochloride) when given alone or in combination with another antihypertensive drug is mg daily given at bedtime to minimize somnolence. If after to weeks of therapy, mg does not give satisfactory result, dose of mg may be given, although most of the effect of guanfacine is seen at mg (see CLINICAL PHARMACOLOGY). Higher daily doses have been used, but adverse reactions increase significantly with doses above mg/day. The frequency of rebound hypertension is low, but it can occur. When rebound occurs, it does so after 2-4 days, which is delayed compared with clonidine hydrochloride. This is consistent with the longer half-life of guanfacine. In most cases, after abrupt withdrawal of guanfacine, blood pressure returns to pretreatment levels slowly (within 2-4 days) without ill effects.

DRUG ABUSE AND DEPENDENCE SECTION.

DRUG ABUSE AND DEPENDENCE. No reported abuse or dependence has been associated with the administration of guanfacine.

DRUG INTERACTIONS SECTION.

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 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). Anticoagulants. Ten patients who were stabilized on oral anticoagulants were given guanfacine, 1-2 mg/day, for weeks. No changes were observed in the degree of anticoagulation.In several well-controlled studies, guanfacine was administered together with diuretics with no drug interactions reported. In the long-term safety studies, guanfacine was given concomitantly with many drugs without evidence of any interactions. The principal drugs given (number of patients in parentheses) were: cardiac glycosides (115), sedatives and hypnotics (103), coronary vasodilators (52), oral hypoglycemics (45), cough and cold preparations (45), NSAIDs (38), antihyperlipidemics (29), antigout drugs (24), oral contraceptives (18), bronchodilators (13), insulin (10), and beta blockers (10).. Drug/Laboratory Test Interactions. No laboratory test abnormalities related to the use of guanfacine have been identified.

GENERAL PRECAUTIONS SECTION.

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.. Sedation. Guanfacine, like other orally active central adrenergic agonists, causes sedation or drowsiness, especially when beginning therapy. These symptoms are dose-related (see ADVERSE REACTIONS). When guanfacine is used with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), the potential for additive sedative effects should be considered. Rebound. Abrupt cessation of therapy with orally active central adrenergic agonists may be associated with increases (from depressed on-therapy levels) in plasma and urinary catecholamines, symptoms of nervousness and anxiety and, less commonly, increases in blood pressure to levels significantly greater than those prior to therapy.

GERIATRIC USE SECTION.

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).

HOW SUPPLIED SECTION.

HOW SUPPLIED. Guanfacine Tablets USP, mg are available as white, round, flat-faced beveled-edge tablets, debossed 48 on one side and plain on the other side. These are supplied: NDC 24658-730-01 Bottles of 100 TabletsGuanfacine Tablets USP, mg are available as yellow, round, flat-faced beveled-edge tablets, debossed 49 on one side and plain on the other side. These are supplied: NDC 24658-731-01 Bottles of 100 TabletsStore at 20-25C (68-77F). [See USP controlled room temperature.] Dispense in tight, light-resistant container. Distributed by:PuraCap Laboratories, LLCDBA Blu PharmaceuticalsFranklin, KY 42134 USAManufactured in USAIssued August 2016MF048ISS08/16OE2589.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Guanfacine hydrochloride tablets are indicated in the management of hypertension. Guanfacine may be given alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.

INFORMATION FOR PATIENTS SECTION.

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.

LABOR & DELIVERY SECTION.

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.

LABORATORY TESTS SECTION.

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

NURSING MOTHERS SECTION.

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 nursing woman. Experiments with rats have shown that guanfacine is excreted in the milk.

OVERDOSAGE SECTION.

OVERDOSAGE. 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 cathartic, was monitored for 24 hours, and was discharged in good health.A 2-year-old male weighing 12 kg, who ingested up to mg of guanfacine, developed lethargy. Gastric lavage (followed by activated charcoal and sorbitol slurry via NG tube) removed some tablet fragments within 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.. Treatment of Overdosage:. Gastric lavage and supportive therapy as appropriate. Guanfacine is not dialyzable in clinically significant amounts (2.4%).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL 1 mg. Guanfacine Tablets USP, mgRx Only100 Tablets. Guanfacine Tablets mg 100.jpg.

PEDIATRIC USE SECTION.

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 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.

PHARMACODYNAMICS SECTION.

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 significant decrease in peripheral resistance and 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 and mg of guanfacine. Long-term use of guanfacine had no effect on growth hormone levels.Guanfacine had no effect on plasma aldosterone. 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 SECTION.

Pharmacokinetics. Relative to an intravenous dose of mg, the absolute oral bioavailability of guanfacine is about 80%. Peak plasma concentrations occur from to 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 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 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.

PRECAUTIONS SECTION.

PRECAUTIONS. 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.. Sedation. Guanfacine, like other orally active central adrenergic agonists, causes sedation or drowsiness, especially when beginning therapy. These symptoms are dose-related (see ADVERSE REACTIONS). When guanfacine is used with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), the potential for additive sedative effects should be considered. Rebound. Abrupt cessation of therapy with orally active central adrenergic agonists may be associated with increases (from depressed on-therapy levels) in plasma and urinary catecholamines, symptoms of nervousness and anxiety and, less commonly, increases in blood pressure to levels significantly greater than those prior to therapy. 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 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). Anticoagulants. Ten patients who were stabilized on oral anticoagulants were given guanfacine, 1-2 mg/day, for weeks. No changes were observed in the degree of anticoagulation.In several well-controlled studies, guanfacine was administered together with diuretics with no drug interactions reported. In the long-term safety studies, guanfacine was given concomitantly with many drugs without evidence of any interactions. The principal drugs given (number of patients in parentheses) were: cardiac glycosides (115), sedatives and hypnotics (103), coronary vasodilators (52), oral hypoglycemics (45), cough and cold preparations (45), NSAIDs (38), antihyperlipidemics (29), antigout drugs (24), oral contraceptives (18), bronchodilators (13), insulin (10), and beta blockers (10).. Drug/Laboratory Test Interactions. No laboratory test abnormalities related to the use of guanfacine have been identified.. 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 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 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 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).

PREGNANCY SECTION.

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.

SPL UNCLASSIFIED SECTION.

Sedation. Guanfacine, like other orally active central adrenergic agonists, causes sedation or drowsiness, especially when beginning therapy. These symptoms are dose-related (see ADVERSE REACTIONS). When guanfacine is used with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), the potential for additive sedative effects should be considered.