Guanabenz

When guanabenz is used with centrally active depressants, such as phenothiazines, barbiturates, and benzodiazepines, the potential for additive sedative effects should be considered.

The disposition of orally administered guanabenz is altered modestly in patients with renal impairment. Guanabenz’s half-life is prolonged and clearance decreased, more so in patients on hemodialysis. The clinical significance of these findings is unknown. Careful monitoring of blood pressure during guanabenz dose titration is suggested in patients with coexisting hypertension and renal impairment.

Guanabenz, like other antihypertensive agents, should be used with caution in patients with severe hepatic failure.

The disposition of orally administered guanabenz is altered in patients with alcohol-induced liver disease. Mean plasma concentrations of guanabenz were higher in these patients than in healthy subjects. The clinical significance of this finding is unknown. However, careful monitoring of blood pressure is suggested when guanabenz is administered to patients with hypertension and coexisting chronic hepatic dysfunction.

Guanabenz, like other antihypertensive agents, should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease.

Pregnancy Category C.

GUANABENZ MAY HAVE ADVERSE EFFECTS ON THE FETUS WHEN ADMINISTERED TO PREGNANT WOMEN. A teratology study in mice has indicated a possible increase in skeletal abnormalities when guanabenz is given orally at doses of 3 to 6 times the maximum recommended human dose of 1.0 mg/kg. These abnormalities, principally costal and vertebral, were not noted in similar studies in rats and rabbits. However, increased fetal loss has been observed after oral guanabenz administration to pregnant rats (14 mg/kg) and rabbits (20 mg/kg). Reproductive studies of guanabenz in rats have shown slightly decreased live-birth indices, decreased fetal survival rate, and decreased pup body weight at oral doses of 6.4 and 9.6 mg/kg. There are no adequate, well-controlled studies in pregnant women. Guanabenz should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when guanabenz is administered to a nursing woman.

Two-year studies were conducted with oral guanabenz administered in the diet to mice and rats. No evidence of carcinogenic potential was seen in mice given doses of up to 11.5 mg/kg/day (41.4 mg/m²/day) or in rats given doses of up to 9.5 mg/kg/day (83.8 mg/m²/day). On a body-weight basis, these doses are 9X and 7X, respectively, the maximum recommended human daily dose (MRHDD) of 64 mg (based on a 50 kg individual). On a body-surface-area basis, these doses are 1X (mice) and 2X (rats) the MRHDD.

In the Salmonella microsome mutagenicity (Ames) test system, guanabenz at 200 to 500 mcg per plate or at 30 to 50 mcg/mL in suspension gave dose-related increases in the number of mutants in one (TA 1537) of five Salmonella typhimurium strains with or without inclusion of rat liver microsomes. No mutagenic activity was seen at doses up to those which inhibit growth in the eukaryotic microorganism, Schizosaccharomyces pombe, or in Chinese hamster ovary cells at doses up to those which were lethal to the cells in culture. In another eukaryotic system, Saccharomyces cerevisiae, guanabenz produced no activity in an assay measuring induction of repairable DNA damage.

Reproductive studies showed a decreased pregnancy rate in rats administered high oral doses (9.6 mg/kg) of guanabenz, suggesting an impairment of fertility. The fertility of treated males (9.6 mg/kg) may also have been affected, as suggested by the decreased pregnancy rate of their mates, even though the females received guanabenz only during the last third of pregnancy.

Patients who receive guanabenz 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.

The incidence of adverse effects has been ascertained from controlled clinical studies conducted in the United States and is based on data from 859 patients who received guanabenz for up to 3 years. There is some evidence that the side effects are doserelated.

The following table shows the incidence of adverse effects, occurring in at least 5% of patients in a study comparing guanabenz to placebo, at a starting dose of 8 mg b.i.d.

In other controlled clinical trials at the starting dose of 16 mg/day in 476 patients, the incidence of dry mouth was slightly higher (38%) and that of dizziness was slightly lower (12%), but the incidence of the most frequent adverse effects was similar to the placebo-controlled trial. Although these side effects were not serious, they led to discontinuation of treatment about 15% of the time. In more recent studies using an initial dose of 8 mg/day in 274 patients, the incidence of drowsiness or sedation was lower, about 20%.

Other adverse effects were reported during clinical trials with guanabenz but are not clearly distinguishable from placebo effects and occurred with a frequency of 3% or less:

Cardiovascular: chest pain, edema, arrhythmias, palpitations.

Gastrointestinal: nausea, epigastric pain, diarrhea, vomiting, constipation, abdominal discomfort.

Central nervous system: anxiety, ataxia, depression, sleep disturbances.

ENT disorders: nasal congestion.

Eye disorders: blurring of vision.

Musculoskeletal: aches in extremities, muscle aches.

Respiratory: dyspnea.

Dermatologic: rash, pruritus.

Urogenital: urinary frequency, disturbances of sexual function (decreased libido, impotence).

Other: gynecomastia, taste disorders.

In very rare instances atrioventricular dysfunction, up to and including complete AV block, has been caused by guanabenz.