Tenex

Name: Tenex

Clinical pharmacology

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.

Mean Changes (mm Hg) from Baseline in Seated Systolic and Diastolic Blood Pressure for Patients Completing 4 to 8 Weeks of Treatment with Guanfacine Monotherapy

Mean Change S/D* Seated n = (range) Placebo 0.5 mg 1 mg 2 mg 3 mg 5 mg
White Patients 11-30 -1/-5 -6/-8 -8/-9 -12/-11 -15/-12 -18/-16
Black Patients 8-28 -3/-5 0/-2 -3/-5 -7/-7 -8/-9 -19/-15
* S/D = Systolic/diastolic blood pressure

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.

Mean Decreases (mm Hg) in Seated and Standing Blood Pressure for Patients Treated with Guanfacine in Combination with Chlorthalidone

Mean Change Placebo 0.5 mg 1 mg 2 mg 3 mg
n = 63 63 64 58 59
SD* Seated -5/-7 -5/-6 -14/-13 -12/-13 -16/-13
SD Standing -3/-5 -5/-4 -11/-9 -9/-10 -15/-12
* S/D = Systolic/diastolic blood pressure

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.

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.

Tenex (guanfacine hydrochloride) 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 Tenex 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 1.0, 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.

Tenex Precautions

  • Do not drive, operate heavy machinery, or do other dangerous activities until you know how Tenex affects you. Tenex can slow your thinking and motor skills.
  • Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking Tenex until you talk with your doctor. Tenex taken with alcohol or medicines that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
  • Tenex may cause serious side effects including low blood pressure, low heart rate, fainting, and sleepiness. Get medical help right away if you experience any of these symptoms.

What should I discuss with my healthcare provider before taking Tenex (guanfacine)?

You should not use this medication if you are allergic to guanfacine.

To make sure you can safely take guanfacine, tell your doctor if you have any of these other conditions:

  • heart disease or heart block;

  • coronary artery disease or a history of stroke;

  • low blood pressure;

  • kidney disease;

  • liver disease; or

  • if you have recently had a heart attack.

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether guanfacine passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Introduction

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

Uses of Tenex

  • It is used to treat high blood pressure.
  • It may be given to you for other reasons. Talk with the doctor.

How do I store and/or throw out Tenex?

  • Store at room temperature.
  • Protect from light.
  • Store in a dry place. Do not store in a bathroom.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Tenex (guanfacine tablets), please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Tenex. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Tenex.

Review Date: October 4, 2017

Tenex - Clinical Pharmacology

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.

Mean Changes (mm Hg) from Baseline in Seated Systolic and Diastolic Blood Pressure for Patients Completing 4 to 8 Weeks of Treatment with Guanfacine Monotherapy
Mean Change S/D* Seated n = (range) Placebo 0.5 mg 1 mg 2 mg 3 mg 5 mg
* S/D = Systolic/diastolic blood pressure
White Patients 11–30 -1/-5 -6/-8 -8/-9 -12/-11 -15/-12 -18/-16
Black Patients 8–28 -3/-5 0/-2 -3/-5 -7/-7 -8/-9 -19/-15


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.

Mean Decreases (mm Hg) in Seated and Standing Blood Pressure for Patients Treated with Guanfacine in Combination with Chlorthalidone
Mean Change n = Placebo
63
0.5 mg
63
1 mg
64
2 mg
58
3 mg
59
* S/D = Systolic/diastolic blood pressure
SD* Seated
-5/-7 -5/-6 -14/-13 -12/-13 -16/-13
SD Standing
-3/-5 -5/-4 -11/-9 -9/-10 -15/-12

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.

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.

Tenex (guanfacine hydrochloride) 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 Tenex 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 1.0, 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.


Drug/Laboratory Test Interactions

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

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 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.

Treatment of Overdosage

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

(web3)