CONTRAINDICATIONS
Terazosin hydrochloride capsules are contraindicated in patients known to be hypersensitive to
terazosin hydrochloride.
WARNINGS
Syncope and "First-Dose" Effect
Terazosin hydrochloride capsules, like other alpha-adrenergic blocking agents, can cause
marked lowering of blood pressure, especially postural hypotension, and syncope in
association with the first dose or first few days of therapy. A similar effect can be
anticipated if therapy is interrupted for several days and then restarted. Syncope has also
been reported with other alpha-adrenergic blocking agents in association with rapid
dosage increases or the introduction of another antihypertensive drug. Syncope is
believed to be due to an excessive postural hypotensive effect, although occasionally the
syncopal episode has been preceded by a bout of severe supraventricular tachycardia,
with heart rates of 120-160 beats per minute. Additionally, the possibility of the
contribution of hemodilution to the symptoms of postural hypotension should be
considered.
To decrease the likelihood of syncope or excessive hypotension, treatment should always
be initiated with a 1-mg dose of terazosin, given at bedtime. The 2, 5, and 10 mg capsules
are not indicated as initial therapy. Dosage should then be increased slowly, according to
recommendations (see DOSAGE AND ADMINISTRATION), and additional
antihypertensive agents should be added with caution. The patient should be cautioned to
avoid situations, such as driving or hazardous tasks, where injury could result should
syncope occur during initiation of therapy.
In early investigational studies, where increasing single doses of up to 7.5 mg were given at 3-day
intervals, tolerance to the first dose phenomenon did not necessarily develop, and the "first dose"
effect could be observed at all doses. Syncopal episodes occurred in 3 of the 14 subjects given
terazosin at doses of 2.5, 5, and 7.5 mg, which are higher than the recommended initial dose. In
addition, severe orthostatic hypotension (blood pressure falling to 50/0 mm Hg) was seen in two
others and dizziness, tachycardia, and lightheadedness occurred in most subjects. These adverse
effects all occurred within 90 minutes of dosing.
In three placebo-controlled BPH studies 1, 2, and 3 (see CLINICAL PHARMACOLOGY), the
incidence of postural hypotension in the terazosin-treated patients was 5.1, 5.2, and 3.7%,
respectively.
In multiple-dose clinical trials involving nearly 2000 hypertensive patients treated with terazosin,
syncope was reported in about 1% of patients. Syncope was not necessarily associated only with
the first dose.
If syncope occurs, the patient should be placed in a recumbent position and treated
supportively, as necessary. There is evidence that the orthostatic effect of terazosin is
greater, even in chronic use, shortly after dosing. The risk of events is greatest during
the initial 7 days of treatment but continues at all time intervals.
Priapism
Rarely (probably less than once in every several thousand patients), terazosin and other
a1-antagonists have been associated with priapism (painful erection, sustained for hours and
unrelieved by sexual intercourse or masturbation). Two or three dozen cases have been reported.
Because this condition can lead to permanent impotence if not promptly treated, patients must be
advised about the seriousness of the condition (see PRECAUTIONS, Information for the Patient).
PRECAUTIONS
General
Prostatic Cancer: Carcinoma of the prostate and BPH cause many of the same symptoms. These
two diseases frequently coexist. Therefore, patients thought to have BPH should be examined prior
to starting terazosin hydrochloride therapy to rule out the presence of carcinoma of the prostate.
Orthostatic Hypotension: While syncope is the most severe orthostatic effect of terazosin (see
WARNINGS), other symptoms of lowered blood pressure such as dizziness, lightheadedness, and
palpitations were more common and occurred in some 28% of patients in clinical trials of
hypertension. In BPH clinical trials, 21% of the patients experienced one or more of the following:
dizziness, hypotension, postural hypotension, syncope, and vertigo. Patients with occupations in
which such events represent potential problems should be treated with particular caution.
Information for the Patient (See PATIENT PACKAGE INSERT.)
Patients should be made aware of the possibility of syncopal and orthostatic symptoms, especially at
the initiation of therapy, and to avoid driving or hazardous tasks for 12 hours after the first dose,
after a dosage increase, and after interruption of therapy when treatment is resumed. They should
be cautioned to avoid situations where injury could result should syncope occur during initiation of
terazosin therapy. They should also be advised of the need to sit or lie down when symptoms of
lowered blood pressure occur, although these symptoms are not always orthostatic, and to be
careful when rising from a sitting or lying position. If dizziness, lightheadedness, or palpitations are
bothersome they should be reported to the physician so that dose adjustment can be considered.
Patients should also be told that drowsiness or somnolence can occur with terazosin, requiring
caution in people who must drive or operate heavy machinery.
Patients should be advised about the possibility of priapism as a result of treatment with terazosin
and other similar medications. Patients should know that this reaction to terazosin is extremely rare,
but that if it is not brought to immediate medical attention, it can lead to permanent erectile
dysfunction (impotence).
Laboratory Tests
Small but statistically significant decreases in hematocrit, hemoglobin, white blood cells, total protein,
and albumin were observed in controlled clinical trials. These laboratory findings suggested the
possibility of hemodilution. Treatment with terazosin for up to 24 months had no significant effect on
prostate specific antigen (PSA) levels.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Terazosin was devoid of mutagenic potential when evaluated in vivo and in vitro (the Ames test,
in vivo cytogenetics, the dominant lethal test in mice, in vivo Chinese hamster chromosome
aberration test, and V79 forward mutation assay).
Terazosin administered in the feed to rats at doses of 8, 40, and 250 mg/kg/day (70, 350, and 2100
mg/m2/day) for 2 years was associated with a statistically significant increase in benign adrenal
medullary tumors of male rats exposed to the 250 mg/kg dose. This dose is 175 times the maximum
recommended human dose of 20 mg (12 mg/m2). Female rats were unaffected. Terazosin was not
oncogenic in mice when administered in feed for 2 years at a maximum tolerated dose of 32
mg/kg/day (110 mg/m2; 9 times the maximum recommended human dose). The absence of
mutagenicity in a battery of tests, of tumorigenicity of any cell type in the mouse carcinogenicity
assay, of increased total tumor incidence in either species, and of proliferative adrenal lesions in
female rats, suggests a male rat species-specific event. Numerous other diverse pharmaceutical
and chemical compounds have also been associated with benign adrenal medullary tumors in male
rats without supporting evidence for carcinogenicity in man.
The effect of terazosin on fertility was assessed in a standard fertility/reproductive performance
study in which male and female rats were administered oral doses of 8, 30, and 120 mg/kg/day.
Four of 20 male rats given 30 mg/kg (240 mg/m2; 20 times the maximum recommended human
dose) and 5 of 19 male rats given 120 mg/kg (960 mg/m2; 80 times the maximum recommended
human dose) failed to sire a litter. Testicular weights and morphology were unaffected by
treatment. Vaginal smears at 30 and 120 mg/kg/day, however, appeared to contain less sperm than
smears from control matings, and good correlation was reported between sperm count and
subsequent pregnancy.
Oral administration of terazosin for 1 or 2 years elicited a statistically significant increase in the
incidence of testicular atrophy in rats exposed to 40 and 250 mg/kg/day (29 and 175 times the
maximum recommended human dose), but not in rats exposed to 8 mg/kg/day (>6 times the
maximum recommended human dose). Testicular atrophy was also observed in dogs dosed with
300 mg/kg/day (>500 times the maximum recommended human dose) for 3 months but not after 1
year when dosed with 20 mg/kg/day (38 times the maximum recommended human dose). This
lesion has also been seen with prazosin, another selective-alpha-1 blocking agent.
Pregnancy Category C
Teratogenic Effects: Terazosin was not teratogenic in either rats or rabbits when administered oral
doses of up to 280 and 60 times, respectively, the maximum recommended human dose. Fetal
resorptions occurred in rats dosed with 480 mg/kg/day, approximately 280 times the maximum
recommended human dose. Increased fetal resorptions, decreased fetal weight, and an increased
number of supernumerary ribs were observed in offspring of rabbits dosed with 60 times the
maximum recommended human dose. These findings (in both species) were most likely secondary
to maternal toxicity. There are no adequate and well-controlled studies in pregnant women, and the
safety of terazosin in pregnancy has not been established. Terazosin hydrochloride is not
recommended during pregnancy unless the potential benefit justifies the potential risk to the mother
and fetus.
Nonteratogenic Effects: In a peri- and postnatal development study in rats, significantly more pups
died in the group dosed with 120 mg/kg/day (>75 times the maximum recommended human dose)
than in the control group during the 3-week postpartum period.
Nursing Mothers
It is not known whether terazosin is excreted in breast milk. Because many drugs are excreted in
breast milk, caution should be exercised when terazosin is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been determined.