Hytrin

In controlled trials, terazosin hydrochloride has been added to diuretics and several beta-adrenergic blockers; except for the additive hypotensive effect, no unexpected interactions were observed. Terazosin hydrochloride has also been used in patients on a variety of concomitant therapies. While these were not formal interaction studies, no interactions were observed. Terazosin hydrochloride has been used concomitantly in at least 50 patients on the following drugs or drug classes: 1) analgesic/anti-inflammatory (e.g., acetaminophen, acetylsalicylic acid, 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., antacid); 9) hypoglycemics; 10) sedatives and tranquilizers (e.g. diazepam).

The dose should be increased in a stepwise fashion at weekly intervals to 2 mg, 5 mg, or 10 mg once daily to achieve the desired improvement of symptoms and/or flow rates. Maintenance doses of 5 to 10 mg once daily are generally required for the clinical response. The duration and dosage of treatment should be carefully titrated. Four weeks of terazosin hydrochloride therapy may be required before statistically significant improvement in the objective parameters of flowmetry (peak urine flow) are obtained. Improvement in the symptoms may appear as early as 2 weeks, but may be delayed as late as six weeks or more. Some patients may not achieve a clinical response despite appropriate titration. Following 18 months of treatment, a complete re-evaluation of the patient's condition should be made.

Following the administration of the maximum recommended dosage, terazosin hydrochloride should be discontinued if improvement in uroflowmetry is not clinically significant from baseline level or improvement in the American Urology Association (AUA) scores are not translated into improvements in quality of life. Terazosin hydrochloride therapy should also be discontinued if terazosin hydrochloride side effects are more bothersome than BPH symptoms or if the patient develops a urinary complication while on terazosin hydrochloride therapy.

1 mg of terazosin hydrochloride at bedtime is the starting dose for all patients, and this dose should not be exceeded for the first week. Compliance with this initial dosage should be strictly observed to minimize the potential for acute hypotensive episodes.

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

Thrombocytopenia has been reported.

constipation, and flatulence.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Adverse Drug Reactions in Clinical Trials Involving Hypertensive Patients on Terazosin Hydrochloride Monotherapy or Combination Therapy

peripheral edema, weight gain.

conjunctivitis.

arthralgia, arthritis, joint disorder, and myalgia.

hypokalemia, hypophosphatemia, decreased libido.

pruritus, rash, photosensitivity.

fever, neck pain, and shoulder pain, anaphylaxis has rarely been reported.

vasodilation, atrial fibrillation has been reported; however, a cause and effect relationship has not been established.

anxiety.

priapism, urinary tract infection, and urinary incontinence primarily reported in post-menopausal women.

bronchitis, epitaxis, and flu symptoms.

gout.

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.

The following events were reported in less than 1% of cases. The order of presentation corresponds within each heading to the relative frequency of occurrence.

HYTRIN has not been studied in children and therefore use in this age group is not recommended.

It is employed in a general treatment program in conjunction with a thiazide diuretic and/or other antihypertensive drugs as needed for proper patient response. HYTRIN may be tried as a sole therapy in those patients in whom other agents caused adverse effects or are inappropriate.

The onset of effect is rapid, with improvement in peak flow rate and symptoms observed at 2 weeks. The effect on these variables was well maintained throughout the study duration (18 months). HYTRIN does not retard or stop the progression of BPH. The long-term effects of HYTRIN on the incidence of surgery, acute urinary obstruction or other complications of BPH, are yet to be determined.

A number of clinical conditions can mimic symptomatic BPH (i.e. stricture of urethra, stricture of bladder neck, urinary bladder stones, neurogenic bladder dysfunction secondary to diabetes, Parkinsonism, etc.). These conditions should therefore be ruled out before terazosin hydrochloride therapy is initiated.

Patients over 75 years of age may have limited benefit from HYTRIN therapy.

Each tan, round tablet contains: terazosin 5 mg (as terazosin HCl dihydrate). Nonmedicinal ingredients: cornstarch, iron oxide, lactose, magnesium stearate, povidone and talc. Alcohol-, gluten-, paraben-, sodium-, sucrose-, sulfite- and tartrazine-free. Starter Pack - one strip (seven) of each 1 mg and 2 mg tablets and, two strips (two times seven) of 5 mg tablets in blisters. Plastic bottles of 100.

One strip (seven) of each 1 mg and 2 mg tablets and, two strips (two times seven) of 5 mg tablets in blisters.

Each blue, round tablet contains: terazosin 10 mg (as terazosin HCl dihydrate). Nonmedicinal ingredients: cornstarch, FD&C Blue No. 2, lactose, magnesium stearate, pregelatinized starch and talc. Alcohol-, gluten-, paraben-, sodium-, sucrose-, sulfite- and tartrazine-free. Plastic bottles of 100.

Each white, round tablet contains: terazosin 1 mg (as terazosin HCl dihydrate). Nonmedicinal ingredients: cornstarch, lactose, magnesium stearate, povidone and talc. Alcohol-, gluten-, paraben-, sodium-, sucrose-, sulfite- and tartrazine-free. Plastic bottles of 100.

Each orange round tablet contains: terazosin 2 mg (as terazosin HCl dihydrate). Nonmedicinal ingredients: cornstarch, FD&C yellow No. 6, lactose, magnesium stearate, povidone and talc. Alcohol-, gluten-, paraben-, sodium-, sucrose-, sulfite- and tartrazine-free. Plastic bottles of 100.

The use of terazosin hydrochloride in patients with impaired renal function requires careful monitoring. Limited pharmacokinetic studies using low doses (1 mg) showed no difference in the pharmacokinetic of terazosin as compared to patients with normal renal function. Approximately 40% of oral terazosin dose is excreted by the kidney as parent drug or metabolites.

Terazosin hydrochloride was devoid of mutagenic potential when evaluated in vivo and in vitro.

Terazosin hydrochloride, administered in the feed to rats at doses of 8, 40, and 250 mg/kg/day for two years, was associated with a statistically significant increase in benign adrenal medullary tumors of male rats exposed to the 250 mg/kg dose. Female rats were unaffected. Terazosin hydrochloride was not oncogenic in mice when administered in feed for 2 years at a maximum tolerated dose of 32 mg/kg/day.

Terazosin hydrochloride should not be prescribed to patients with symptomatic BPH who have the following concomitant conditions: chronic urinary retention, high residual urine (over 200 mL), peak urine flow of 5 mL/sec or less, history of prior prostatic surgery, chronic fibrous or granulomatous prostatitis, urethral stricture, history of pelvic irradiation, presence of prostatic calculi, presence of large median lobe of prostate, presence of calculi in urinary bladder, recent history of epididymitis, gross hematuria, presence of neurogenic bladder dysfunction (diabetes mellitus, Parkinsonism, uninhibited neurogenic bladder, etc.), hydro-nephrosis, presence of carcinoma of the prostate, patients with clinically significant renal or hepatic impairment (i.e. serum creatinine >2 mg/dL or AST >1.5 times the upper limit of normal (or equivalent level on the international scale).

Terazosin hydrochloride can cause marked hypotension, especially postural hypotension, and syncope in association with the first dose or first few doses of therapy. A similar effect can occur if therapy is re-instated following interruption for more than a few doses. Syncope has also occurred in association with rapid dosage increases or the introduction of another antihypertensive agent into the regimen of a patient taking high doses of terazosin hydrochloride.

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.

In studies of terazosin hydrochloride the incidence of syncopal episodes was approximately 1% in hypertensive patients and 0.7% in patients with BPH.

The likelihood of syncopal episodes or excessive hypotension can be minimized by limiting the initial dose of the drug to 1 mg of terazosin hydrochloride given at bedtime, by increasing the dosage slowly, and by introducing any additional antihypertensive drugs into the patient's regimen with caution (see Dosage and Administration).

Patients should be advised of the possibility of syncopal and orthostatic symptoms, and to avoid driving or hazardous tasks for 12 hours after the initial dose of terazosin hydrochloride, after the dose is increased and after interruption of therapy when treatment is resumed. They should be cautioned to avoid situations where injury could result should syncope occur.

If syncope occurs, place the patients in the recumbent position and institute supportive measures as necessary.

Patients with a history of micturition syncope should not receive terazosin hydrochloride.

Concomitant administration of terazosin hydrochloride with verapamil to hypertensive patients may result in symptomatic hypotension and in some cases tachycardia (see Warnings and Precautions).

While syncope is the most severe orthostatic effect of terazosin hydrochloride (see Warnings and Precautions, Cardiovascular) other symptoms of lowered blood pressure, such as dizziness, lightheadedness and palpitations are more common with one or more of these occurring in 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 should be advised to lie down when these symptoms occur and then wait for a few minutes before standing to prevent their recurrence.

Patients with occupation in which such events represent potential problems should be treated with particular caution.

There is evidence that the orthostatic effect of terazosin hydrochloride is greater, even in chronic use, shortly after dosing.

The safety of terazosin hydrochloride in pregnancy has not been established. Terazosin hydrochloride is not recommended during pregnancy unless potential benefits justifies potential risks to mother and fetus.

In animal studies there was no teratogenic effect. In peri- and post-natal development studies in rats, significantly more pups died in the group dosed with 120 mg/kg/day than in the control group during the three week postpartum period.

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.

Caution is advised when PDE5 inhibitors such as VIAGRA (sildenafil), CIALIS (tadalafil) and LEVITRA (vardenafil) are co-administered with alpha-blockers. Both PDE5 inhibitors and alpha-adrenergic blocking agents are vasodilators with blood pressure lowering effects. When vasodilators are used in combination, additive effects on blood pressure may be anticipated. In some patients, concomitant use of these two classes of drugs can lower blood pressure significantly, which may lead to symptomatic hypotension. Consideration should be given to the following:

• Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.

  
  

• In patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose.

  
  

• Safety of combined use of PDE5 inhibitors and alpha-blockers may be adversely affected by other factors, such as intravascular volume depletion and other antihypertensive therapy.

Terazosin hydrochloride should be used cautiously in elderly patients because of the possibility of orthostatic hypotension. There was an age-related trend towards an increased incidence of dizziness, blurred vision and syncope in elderly patients treated with this drug. Patients over seventy-five years of age may have limited benefit from terazosin hydrochloride therapy.

Fluid retention resulting in weight gain may occur during terazosin hydrochloride therapy. In placebo-controlled monotherapy trials, male and female patients receiving terazosin hydrochloride gained a mean 0.8 and 1 kg respectively, compared to losses of 0.1 and 0.5 kg respectively, in the placebo group. Both differences are significant.

HYTRIN (terazosin hydrochloride) therapy does not modify the natural history of benign protatic hyperplasia (BPH). It does not retard or stop the progression of BPH, nor does it improve urine flow sufficiently to significantly reduce the residual urine volume. However, significant reduction of the mean residual volume have been shown in patients with baseline residual volumes of >50 mL. The patient may continue to be at risk of developing urinary retention and other BPH complications during terazosin hydrochloride therapy.

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.

Anaphylactoid-like reactions manifested by angioedema of the lips, tongue, pharynx, and/or laryngeal spasm have been rarely reported in patients treated with terazosin hydrochloride (see Adverse Reactions). In such cases, terazosin hydrochloride should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred.

Long-term (6 months or longer) administration of terazosin hydrochloride has produced no pattern of clinically significant changes attributable to the drug in the following clinical laboratory measurements: glucose, uric acid, creatinine, BUN, liver function tests, and electrolytes.

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 hydrochloride for up to 24 months had no significant effect on prostate specific antigen (PSA) levels.

The use of terazosin hydrochloride in children is not recommended since safety and efficacy have not been established.

Effect 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 and five of 19 male rats given 120 mg/kg failed to sire a litter. Testicular weights and morphology were unaffected by treatment. Vaginal smears at 30 and 120 mg/kg, 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 hydrochloride for one or two years elicited a statistically significant increase in the incidence of testicular atrophy in rats exposed to 40 and 250 mg/kg/day, but not in rats exposed to 8 mg/kg/day. Testicular atrophy was also observed in dogs dosed with 300 mg/kg/day for 3 months but not after one year when dosed with 20 mg/kg/day.

It is not known whether terazosin is excreted in human milk. Because of possible adverse reactions in nursing infants an alternate method of infant feeding should be considered when the use of drug is essential.

No information is available on the use of terazosin hydrochloride in patients with impaired liver function.

In a study that evaluated the effect of age on terazosin hydrochloride pharmacokinetics, the mean plasma half-lives were 14.0 and 11.4 hours for the age group ≥70 years and the age group 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.

Orally administered terazosin hydrochloride is essentially completely absorbed in man. Nearly all of the circulating dose is in the form of parent drug. Food has little or no effect on the bioavailability. The plasma levels of the free base peak in about 1 hour and then decline with a t_½ of approximately 12 hours.

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. Overall approximately 40% of the administered dose is excreted in the urine and approximately 60% in the feces.

Impaired renal function had no significant effect on the elimination of terazosin hydrochloride, and dosage adjustment of terazosin hydrochloride to compensate for the drug removal during hemodialysis (approximately 10%) does not appear to be necessary.

Approximately 90 to 94% of the drug is bound to plasma proteins and binding is constant over the clinically observed concentration range. Hepatic metabolism is extensive with major biliary elimination.

Systolic and diastolic blood pressure is lowered in both the supine and standing positions. In clinical trials, blood pressure responses were measured at the end of the dosing interval (24 hours), with the usual supine response 5 to 10 mmHg systolic and 3.5 to 8 mmHg diastolic. The response in the standing position tended to be larger by 1 to 3 mmHg.

Limited measurements of peak response (2 to 3 hours after dosing) during chronic terazosin hydrochloride administration indicate that this response is somewhat greater than the trough (24-hour) response, suggesting some attenuation of response at 24 hours, presumably due to a fall in blood terazosin concentrations at the end of the dose interval.

The greater blood pressure effect associated with peak plasma concentrations appears to be more position dependent (greater in the standing position) than the effect of terazosin hydrochloride at 24 hours; in the standing position there is also a 6 to 10 beat per minute increase in heart rate in the first few hours after dosing. During the first 3 hours after dosing 12.5% of patients had a systolic pressure fall of 30 mmHg or more from supine to standing, or standing systolic pressure below 90 mm Hg with a fall of at least 20 mmHg.

During controlled clinical studies, patients receiving terazosin hydrochloride monotherapy had a small but statistically significant decrease (a 3% fall) compared to placebo in total cholesterol and the combined low-density and very-low density lipoprotein fractions. No significant changes were observed in high-density lipoprotein fraction and triglycerides compared to placebo.

The symptoms associated with BPH are related to bladder outlet obstruction. The bladder outlet obstruction is comprised of a static obstruction due to the enlarged prostate and a dynamic obstruction which is dependent upon the sympathetically controlled tone of the smooth muscle in the prostate and the bladder neck. Stimulation of alpha-1 adrenoceptors in the smooth muscle of the bladder neck and the prostate causes smooth muscle contraction and an increase in muscle tone.

In three placebo-controlled studies in men with symptomatic BPH, symptom evaluation and uroflowmetric measurements were performed approximately 24 hours following dosing. Results from these studies indicated that terazosin hydrochloride significantly improved symptoms and peak urine flow rates over placebo.

In 30 to 70% of patients with symptomatic BPH, placebo has also shown a remarkable and sometimes dramatic effect in controlled short-term studies. The symptoms may subside or fade away without treatment in approximately 20% of patients.