rsi ad
 
drx ad
 
ad space

Terazosin Hydrochloride Tablets

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Terazosin hydrochloride, an alpha-1-selective adrenoceptor blocking agent, is a quinazoline derivative represented by the following structural formula, molecular formula and chemical name:

(RS)-Piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(tetra-hydro-2-furanyl)carbonyl]-, monohydrochloride, dihydrate.

Terazosin hydrochloride is a white, crystalline substance, freely soluble in water and isotonic saline and has a molecular weight of 459.93.

Terazosin hydrochloride tablets for oral ingestion are supplied in four dosage strengths containing terazosin hydrochloride equivalent to 1 mg, 2 mg, 5 mg, or 10 mg of terazosin.

Inactive Ingredients:

1 mg tablet: corn starch, lactose, magnesium stearate, povidone and talc.

2 mg tablet: corn starch, FD&C Yellow No. 6, lactose, magnesium stearate, povidone and talc.

5 mg tablet: corn starch, iron oxide, lactose, magnesium stearate, povidone and talc.

10 mg tablet: corn starch, D&C Yellow No. 10, FD&C Blue No. 2, lactose, magnesium stearate, povidone and talc.

2. INDICATIONS AND USAGE

2.1 Benign prostatic hyperplasia (BPH)

Terazosin hydrochloride is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH). There is a rapid response, with approximately 70% of patients experiencing an increase in urinary flow and improvement in symptoms of BPH when treated with terazosin hydrochloride. The long-term effects of terazosin hydrochloride on the incidence of surgery, acute urinary obstruction or other complications of BPH are yet to be determined.

2.2 Hypertension

Terazosin hydrochloride is also indicated for the treatment of hypertension. It can be used alone or in combination with other antihypertensive agents such as diuretics or beta-adrenergic blocking agents.

3. DOSAGE AND ADMINISTRATION

If terazosin hydrochloride administration is discontinued for several days, therapy should be reinstituted using the initial dosing regimen.

3.1 Benign Prostatic Hyperplasia

Initial Dose

1 mg at bedtime is the starting dose for all patients, and this dose should not be exceeded as an initial dose. Patients should be closely followed during initial administration in order to minimize the risk of severe hypotensive response.

Subsequent Doses

The dose should be increased in a stepwise fashion to 2 mg, 5 mg, or 10 mg once daily to achieve the desired improvement of symptoms and/or flow rates. Doses of 10 mg once daily are generally required for the clinical response. Therefore, treatment with 10 mg for a minimum of 4 to 6 weeks may be required to assess whether a beneficial response has been achieved. Some patients may not achieve a clinical response despite appropriate titration. Although some additional patients responded at a 20 mg daily dose, there was an insufficient number of patients studied to draw definitive conclusions about this dose. There are insufficient data to support the use of higher doses for those patients who show inadequate or no response to 20 mg daily. If terazosin hydrochloride administration is discontinued for several days or longer, therapy should be reinstituted using the initial dosing regimen.

Use With Other Drugs

Caution should be observed when terazosin hydrochloride is administered concomitantly with other antihypertensive agents, especially the calcium channel blocker verapamil, to avoid the possibility of developing significant hypotension. When using terazosin hydrochloride and other antihypertensive agents concomitantly, dosage reduction and retitration of either agent may be necessary (see PRECAUTIONS). Hypotension has been reported when terazosin has been used with phosphodiesterase-5 (PDE-5) inhibitors.

3.2 Hypertension

The dose of terazosin hydrochloride and the dose interval (12 or 24 hours) should be adjusted according to the patient's individual blood pressure response. The following is a guide to its administration:

Initial Dose

1 mg at bedtime is the starting dose for all patients, and this dose should not be exceeded. This initial dosing regimen should be strictly observed to minimize the potential for severe hypotensive effects.

Subsequent Doses

The dose may be slowly increased to achieve the desired blood pressure response. The usual recommended dose range is 1 mg to 5 mg administered once a day; however, some patients may benefit from doses as high as 20 mg per day. Doses over 20 mg do not appear to provide further blood pressure effect and doses over 40 mg have not been studied. Blood pressure should be monitored at the end of the dosing interval to be sure control is maintained throughout the interval. It may also be helpful to measure blood pressure 2 to 3 hours after dosing to see if the maximum and minimum responses are similar, and to evaluate symptoms such as dizziness or palpitations which can result from excessive hypotensive response. If response is substantially diminished at 24 hours an increased dose or use of a twice daily regimen can be considered. If terazosin hydrochloride administration is discontinued for several days or longer, therapy should be reinstituted using the initial dosing regimen. In clinical trials, except for the initial dose, the dose was given in the morning.

Use With Other Drugs

(see above)

4. CONTRAINDICATIONS

Terazosin hydrochloride capsules are contraindicated in patients known to be hypersensitive to terazosin hydrochloride.

5. MECHANISM OF ACTION

Terazosin hydrochloride is an alpha-1-selective adrenoceptor blocking agent. The exact mechanism of action of terazosin is unknown.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

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.

6.2 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.

6.3 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

7. WARNINGS AND PRECAUTIONS

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 alphaadrenergic 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 to 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 mg, 5 mg and 10 mg capsules are not indicated as initial therapy. Dosage should then be increased slowly, according to recommendations in the Dosage and Administration section 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 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 mg, 5 mg and 7.5 mg, which are higher than the recommended initial dose; in addition, severe orthostatic hypotension (blood pressure falling to 50/0 mmHg) 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, 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 2,000 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 the events is greatest during the initial seven 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 penile 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 Patients).

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.

Intraoperative Floppy Iris Syndrome (IFIS)

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on/or previously treated with alpha-1 blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient's ophthalmologist should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.

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 Patients

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.

8. ADVERSE REACTIONS

The prevalence rates presented below are based on combined data from fourteen placebo-controlled trials involving once a day administration of terazosin, as monotherapy or in combination with other antihypertensive agents, at doses ranging from 1 mg to 40 mg. Table 1 summarizes those adverse experiences reported for patients in these trials where the prevalence rate in the terazosin group was at least 5%, where the prevalence rate for the terazosin group was at least 2% and was greater than the prevalence rate for the placebo group, or where the reaction is of particular interest. Asthenia, blurred vision, dizziness, nasal congestion, nausea, peripheral edema, palpitations and somnolence were the only symptoms that were significantly (p < 0.05) more common in patients receiving terazosin than in patients receiving placebo. Similar adverse reaction rates were observed in placebo-controlled monotherapy trials.

TABLE 1. ADVERSE REACTIONS DURING PLACEBO-CONTROLLED TRIALS

Post-Marketing Experience

Post-marketing experience indicates that in rare instances patients may develop allergic reactions, including anaphylaxis, following administration of terazosin hydrochloride. There have been reports of priapism and thrombocytopenia during post-marketing surveillance. Atrial fibrillation has been reported. During cataract surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) has been reported in association with alpha-1 blocker therapy (see PRECAUTIONS).

9. OVERDOSAGE

Should overdosage of terazosin hydrochloride lead to hypotension, support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position. If this measure is inadequate, shock should first be treated with volume expanders. If necessary, vasopressors should then be used and renal function should be monitored and supported as needed. Laboratory data indicate that terazosin is 90 to 94% protein bound; therefore, dialysis may not be of benefit.

10. DRUG INTERACTIONS

In controlled trials, terazosin has been added to diuretics, and several beta-adrenergic blockers; no unexpected interactions were observed. Terazosin has also been used in patients on a variety of concomitant therapies; while these were not formal interaction studies, no interactions were observed. Terazosin has been used concomitantly in at least 50 patients on the following drugs or drug classes:

1) Analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine, ibuprofen, indomethacin);

2) Antibiotics (e.g., erythromycin, trimethoprim and sulfamethoxazole);

3) Anticholinergic/sympathomimetics (e.g., phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride);

4) Antigout (e.g., allopurinol);

5) Antihistamines (e.g., chlorpheniramine);

6) Cardiovascular agents (e.g., atenolol, hydrochlorothiazide, methyclothiazide, propranolol);

7) Corticosteroids;

8) Gastrointestinal agents (e.g., antacids);

9) Hypoglycemics;

10) Sedatives and tranquilizers (e.g., diazepam).

Use with Other Drugs

In a study (n=24) where terazosin and verapamil were administered concomitantly, terazosin's mean AUC0-24 increased 11% after the first verapamil dose and after 3 weeks of verapamil treatment it increased by 24% with associated increases in Cmax (25%) and Cmin (32%) means. Terazosin mean Tmax decreased from 1.3 hours to 0.8 hours after 3 weeks of verapamil treatment. Statistically significant differences were not found in the verapamil level with and without terazosin. In a study (n=6) where terazosin and captopril were administered concomitantly, plasma disposition of captopril was not influenced by concomitant administration of terazosin and terazosin maximum plasma concentrations increased linearly with dose at steady-state after administration of terazosin plus captopril (see DOSAGE AND ADMINISTRATION).

11. PHARMACOKINETICS

Terazosin hydrochloride administered as a capsule is essentially completely absorbed in man. Administration of capsules immediately after meals had a minimal effect on the extent of absorption. The time to reach peak plasma concentration however, was delayed by about 40 minutes. Terazosin has been shown to undergo minimal hepatic first-pass metabolism and nearly all of the circulating dose is in the form of parent drug. The plasma levels peak about one hour after dosing, and then decline with a half-life of approximately 12 hours.

In a study that evaluated the effect of age on terazosin pharmacokinetics, the mean plasma half-lives were 14 and 11.4 hours for the age group ≥ 70 years and the age group of 20 to 39 years, respectively. After oral administration the plasma clearance was decreased by 31.7% in patients 70 years of age or older compared to that in patients 20 to 39 years of age.

The drug is 90 to 94% bound to plasma proteins and binding is constant over the clinically observed concentration range.

Approximately 10% of an orally administered dose is excreted as parent drug in the urine and approximately 20% is excreted in the feces. The remainder is eliminated as metabolites. Impaired renal function had no significant effect on the elimination of terazosin, and dosage adjustment of terazosin to compensate for the drug removal during hemodialysis (approximately 10%) does not appear to be necessary. Overall, approximately 40% of the administered dose is excreted in the urine and approximately 60% in the feces. The disposition of the compound in animals is qualitatively similar to that in man.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: HYTRIN, by ABBOTT.

b) Generic drugs:

Capsules: Terazosin Hydrochloride, by various manufacturers (See Terazosin HCl Capsules).

Tablets: NONE.

2) How Supplied:

HYTRIN tablets (terazosin hydrochloride tablets) are available in four dosage strengths:

1 mg, white tablets (bears the Abbott “A” logo and the Abbo-Code DF): Bottles of 100 (NDC 0074-3322-13).

2 mg, orange tablets (bears the Abbott “A” logo and the Abbo-Code DH): Bottles of 100 (NDC 0074-3323-13).

5 mg, tan tablets (bears the Abbott “A” logo and the Abbo-Code DJ): Bottles of 100 (NDC 0074-3324-13).

10 mg, green tablets (bears the Abbott “A” logo and the Abbo-Code DI): Bottles of 100 (NDC 0074-3325-13).

3) Storage:

Store at below 86°F (30°C).

Rx only

Rev 07/09