TENEX

Tenex (guanfacine hydrochloride) is a centrally acting antihypertensive with α₂-adrenoceptor agonist properties in tablet form for oral administration.

The chemical name of Tenex (guanfacine hydrochloride) is N-amidino- 2-(2,6-dichlorophenyl) acetamide hydrochloride and its molecular weight is 282.56. Its structural formula is:

structure

Guanfacine hydrochloride is a white to off-white powder; sparingly soluble in water and alcohol and slightly soluble in acetone. The tablets contain the following inactive ingredients:

1 mg—FD&C Red 40 aluminum lake, lactose, microcrystalline cellulose, povidone, stearic acid.

2 mg—D&C Yellow 10 aluminum lake, lactose, microcrystalline cellulose, povidone, stearic acid.

Tenex (guanfacine hydrochloride) is an orally active antihypertensive agent whose principal mechanism of action appears to be stimulation of central α₂-adrenergic receptors. By stimulating these receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate.

The dose-response relationship for blood pressure and adverse effects of guanfacine given once a 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, 1 mg, 2 mg, 3 mg, or 5 mg of Tenex. Results are shown in the following table. A useful effect was not observed overall until doses of 2 mg were reached, although responses in white patients were seen at 1 mg; 24 hour effectiveness of 1 mg to 3 mg doses was documented using 24 hour ambulatory monitoring. While the 5 mg dose added an increment of effectiveness, it caused an unacceptable increase in adverse reactions.

Controlled clinical trials in patients with mild to moderate hypertension who were receiving a 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 a 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 3 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 3 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.

While most of the effectiveness of guanfacine in combination (and as monotherapy in white patients) was present at 1 mg, adverse reactions at this dose were not clearly distinguishable from those associated with placebo. Adverse reactions were clearly present at 2 and 3 mg (see ADVERSE REACTIONS).

In a second 12-week placebo-controlled study of 1, 2 or 3 mg of Tenex (guanfacine hydrochloride) administered with 25 mg of chlorthalidone once daily, a significant decrease in blood pressure was maintained for a 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 a 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 a rapid return of diastolic and especially systolic blood pressure to approximately pretreatment levels, with occasional values significantly greater than baseline, whereas guanfacine withdrawal produced a more gradual increase to pretreatment levels, but also with occasional values significantly greater than baseline.

Tenex (guanfacine hydrochloride) is indicated in the management of hypertension. Tenex may be given alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.

Tenex is contraindicated in patients with known hypersensitivity to guanfacine hydrochloride.

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

Tenex, like other orally active central α₂-adrenergic agonists, causes sedation or drowsiness, especially when beginning therapy. These symptoms are dose-related (see ADVERSE REACTIONS). When Tenex is used with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), the potential for additive sedative effects should be considered.

Abrupt cessation of therapy with orally active central α₂-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.

Patients who receive Tenex 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.

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

The potential for increased sedation when Tenex 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).

Ten patients who were stabilized on oral anticoagulants were given guanfacine, 1 - 2 mg/day, for 4 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, Tenex 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).

No laboratory test abnormalities related to the use of Tenex (guanfacine hydrochloride) have been identified.

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.

Adverse reactions noted with Tenex (guanfacine hydrochloride) are similar to those of other drugs of the central α₂-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 a few cases; although clear cause and effect relationships to Tenex could not be established, should a rash occur, Tenex 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 a dose relationship from 0.5 to 3 mg as follows:

The percent of patients who dropped out because of adverse reactions are shown below for each dosage group.

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 a clear dose relationship from 0.5 to 3 mg as follows:

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:

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 a second 12-week placebo-controlled combination therapy study in which the dose could be adjusted upward to 3 mg per day in 1-mg increments at 3-week intervals, i.e., a 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 reactions occurring in 3% or less of patients in the three controlled trials of Tenex (guanfacine hydrochloride) with a diuretic were:

Cardiovascular- bradycardia, palpitations, substernal pain

Gastrointestinal- abdominal pain, diarrhea, dyspepsia, dysphagia, nausea

CNS- amnesia, confusion, depression, insomnia, libido decrease

ENT disorders- rhinitis, taste perversion, tinnitus

Eye disorders- conjunctivitis, iritis, vision disturbance

Musculoskeletal- leg cramps, hypokinesia

Respiratory- dyspnea

Dermatologic- dermatitis, pruritus, purpura, sweating

Urogenital- testicular disorder, urinary incontinence

Other- malaise, paresthesia, paresis

Adverse reaction reports tend to decrease over time. In an open-label trial of one year's 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.

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).

An open-label postmarketing study involving 21,718 patients was conducted to assess the safety of Tenex (guanfacine hydrochloride) 1 mg/day given at bedtime for 28 days. Tenex 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 Tenex-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 BILLIARY SYSTEM abnormal liver function tests

MUSCULO-SKELETAL SYSTEM arthralgia, leg cramps, leg pain, myalgia

PSYCHIATRIC agitation, anxiety, confusion, depression, insomnia, nervousness

RREPRODUCTIVE 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 Tenex 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.

No reported abuse or dependence has been associated with the administration of Tenex (guanfacine hdyrochloride).

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.

Gastric lavage and supportive therapy as appropriate. Guanfacine is not dialyzable in clinically significant amounts (2.4%).

The recommended initial dose of Tenex (guanfacine hydrochloride) when given alone or in combination with another antihypertensive drug is 1 mg daily given at bedtime to minimize somnolence. If after 3 to 4 weeks of therapy 1 mg does not give a satisfactory result, a dose of 2 mg may be given, although most of the effect of Tenex is seen at 1 mg (see CLINICAL PHARMACOLOGY). Higher daily doses have been used, but adverse reactions increase significantly with doses above 3 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.

Tenex^® (guanfacine hydrochloride) Tablets are available in the following dosing strengths (expressed in equivalent amounts of guanfacine):

1 mg—light pink, diamond-shaped tablet embossed with a 1 and engraved RP on one side and engraved TENEX on the other side in bottles of 100 (NDC 67857-705-01) and 500 (NDC 67857-705-05).

2 mg—yellow, diamond-shaped tablet, one side engraved TENEX, other side engraved 2 with RP below it in bottles of 100 (NDC 67857-706-01).

Store at controlled temperature, between 20ଌ and 25°C (68°F and 77°F).

Dispense in a tight, light-resistant container.

Distributed by:
Promius Pharma, LLC
Bridgewater, NJ 08807

Manufactured by:
PATHEON, Puerto Rico, Inc.
Manati, Puerto Rico 00674, USA

Revised: May 2013

NDC-67857-706-01 100 Tablets

TENEX®

(Guanfancine HCL)

equivalent to
2 mg guanfancine

Rx only

PROMIUS PHARMA

label

NDC-67857-705-05 500 Tablets

TENEX®

(Guanfancine HCL)

equivalent to
1 mg guanfancine

Rx only

PROMIUS PHARMA

Tenex1mg