Hytrin (Terazosin HCl)

HYTRIN®

Abbott

Terazosin HCl

Antihypertensive – Symptomatic Treatment of Benign Prostatic Hyperplasia (BPH)

Action And Clinical Pharmacology: Hypertension: The antihypertensive effect of terazosin is believed to be a direct result of peripheral vasodilation. Although the exact mechanism by which the lowering of blood pressure is achieved is not known, the relaxation of the vessels appears to be produced mainly by selective blockade of alpha-1-adrenoceptors.

Benign Prostatic Hyperplasia (BPH): The reduction in the symptoms associated with BPH following administration of terazosin may be related to the changes in muscle tone produced by a blockade of alpha1-adrenoceptors in the smooth muscle of the bladder neck and prostate.

Pharmacodynamics: Hypertension: 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 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 at 24 hours; in the standing position there is also a 6 to 10 beat/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 mmHg with a fall of at least 20 mmHg.

During controlled clinical studies, patients receiving terazosin 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.

Benign Prostatic Hyperplasia (BPH): 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 alpha1-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 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.

Pharmacokinetics: Orally administered terazosin 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 half-life of approximately 12 hours. 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. 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.

Indications And Clinical Uses: Hypertension: Terazosin is indicated in the treatment of mild to moderate hypertension. 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. Terazosin may be tried as a sole therapy in those patients in whom other agents caused adverse effects or are inappropriate.

Benign Prostatic Hyperplasia (BPH): Terazosin is also indicated for the treatment of symptoms of benign prostatic hyperplasia (BPH). 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). Terazosin does not retard or stop the progression of BPH. The long-term effects of terazosin 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 therapy is initiated.

Contra-Indications: In individuals who have shown hypersensitivity to terazosin or its analogs.

Manufacturers’ Warnings In Clinical States: Syncope and “First Dose” Effect: Terazosin 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.

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/minute.

In studies of terazosin 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 given at bedtime, by increasing the dosage slowly, and by introducing any additional antihypertensive drugs into the patient’s regimen with caution (see Dosage).

Occupational Hazards: 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, 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.

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

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

Precautions: General: Terazosin therapy does not modify the natural history of benign prostatic 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 therapy.

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

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

Concomitant Conditions: Terazosin 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/second 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).

Carcinogenesis, Mutagenesis, Impairment of Fertility: Terazosin was devoid of mutagenic potential when evaluated in vivo and in vitro.

Terazosin, administered in the feed to rats at doses of 8, 40, and 250 mg/kg/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. Female rats were unaffected. The drug was not oncogenic in mice when administered in feed for 2 years at a maximum tolerated dose of 32 mg/kg/day.

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 5 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 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, 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 1 year when dosed with 20 mg/kg/day.

Geriatrics: Terazosin 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 75 years of age may have limited benefit from terazosin therapy.

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

Patients with Renal Impairment: The use of terazosin in patients with impaired renal function requires careful monitoring. Limited pharmacokinetic studies using low doses (1 mg) showed no difference in the pharmacokinetics 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.

Patients with Liver Impairment: No information is available on the use of terazosin in patients with impaired liver function.

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

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

In animal studies there was no teratogenic effect. In peri and postnatal development studies in rats, significantly more pups died in the group dosed with 120 mg/kg/day than in the control group during the 3 week postpartum period.

Lactation: 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 the drug is essential.

Drug Interactions: In controlled trials, terazosin has been added to diuretics and several beta-adrenergic blockers; except for the additive hypotensive effect, 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: analgesic/anti-inflammatory (e.g., acetaminophen, ASA, codeine, ibuprofen, indomethacin); antibiotics (e.g. erythromycin, trimethoprim and sulfamethoxazole); anticholinergic/sympathomimetics (e.g., phenylephrine HCl, phenylpropanolamine HCl, pseudoephedrine HCl); antigout (e.g., allopurinol); antihistamines (e.g., chlorpheniramine); cardiovascular agents (e.g., atenolol, hydrochlorothiazide, methyclothiazide, propranolol); corticosteroids; gastrointestinal agents (e.g., antacid); hypoglycemics; sedatives and tranquilizers (e.g., diazepam).

Concomitant administration of terazosin with verapamil to hypertensive patients resulted in significant increases in AUC, Cmax and Cmin of terazosin. The pharmacokinetics of verapamil were not altered. Symptomatic hypotension, and in some cases tachycardia, were observed. Caution should therefore be exercised when these drugs are administered concomitantly (see Warnings).

Laboratory Tests: Long-term (6 months or longer) administration of terazosin 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 for up to 24 months had no significant effect on prostate specific antigen (PSA) levels.

Adverse Reactions: Hypertension: The incidence of adverse reactions is derived from clinical trials involving 1 986 hypertensive patients on terazosin monotherapy or combination therapy.

The most serious adverse reaction encountered with terazosin is syncope occurring in approximately 1% of patients.

The most common reactions were dizziness (18.9%), headache (14.1%), asthenia (11%), somnolence (4.8%), nasal congestion (4.6%) and palpitation (4.6%).

The most frequently reported adverse effects which resulted in termination of the drug were dizziness 3.5%, asthenia 2.1% and headache 1.8%.

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

Body as a Whole: headache (14.1%), asthenia (11%), peripheral edema (3.6%), chest pain (2.2%), abdominal pain (1.5%), edema (1.3%), facial edema (1%), back pain, weight gain, allergic reactions, malaise.

Cardiovascular: palpitation (4.6%), tachycardia (2.9%), syncope (1%), postural hypotension, angina pectoris, arrhythmias, cerebrovascular accident, heart failure, hypotension (at times severe), migraine.

Digestive: nausea (3.9%), dry mouth (1.7%), diarrhea (1.3%), dyspepsia, vomiting, anorexia, gastritis, liver function abnormality, jaundice.

Nervous System: dizziness (18.9%), somnolence (4.8%), nervousness (2.2%), paresthesia (1.5%), insomnia (1.2%), incoordination, abnormal dreams, confusion, speech disorder, tremor, vertigo, seizure, depression.

Respiratory: nasal congestion (4.6%), dyspnea (2.8%), rhinitis (1.2%), sinusitis, cold symptoms, pharyngitis, asthma, increased cough, laryngeal spasm.

Skin and Appendages: sweating (1.1%), pruritus, rash, photosensitivity.

Special Senses: blurred vision (1.4%), eye disorder (1.2%), tinnitus, taste perversion.

Urogenital: impotence (1.1%), urinary frequency, dysuria.

Miscellaneous: pain in extremities (1.8%), hypokalemia, hypophosphatemia, decreased libido.

Postmarketing Experience: Body as a whole: fever, neck pain and shoulder pain anaphylaxis has rarely been reported. Cardiovascular System: vasodilation, atrial fibrillation has been reported; however, a cause and effect relationship has not been established. Digestive System: constipation and flatulence. Nervous System: anxiety. Respiratory System: bronchitis, epistaxis, and flu symptoms. Special Senses: conjunctivitis. Urogenital System: priapism, urinary tract infection, and urinary incontinence primarily reported in postmenopausal women. Musculoskeletal System: arthralgia, arthritis, joint disorder, and myalgia. Hematopoietic System: Thrombocytopenia has been reported. Metabolic/Nutritional Disorders: gout.

Benign Prostatic Hyperplasia (BPH): In clinical trials involving 1 171 patients with BPH, syncope was reported in 0.7% of patients following treatment with terazosin.

The most common reactions (³ 1%) were dizziness (14%), asthenia (9%), headache (6.4%), somnolence (4.5%), postural hypotension (3.8%), impotence (3.5%), urinary tract infection (3.1%), pharyngitis (2.7%), dyspnea (2.5%), rhinitis (2.2%), dysuria (2%), back pain (1.8%), nausea (1.8%), flu syndrome (1.7%), rash (1.7%), sinusitis (1.7%), hypotension (1.5%), chest pain (1.5%), vertigo (1.3%), dyspepsia (1.1%), diarrhea (1%), palpitation (1%), abdominal pain (1%) and amblyopia (1%).

Postmarketing Experience: Thrombocytopenia has been reported. Atrial fibrillation has been reported; however, a cause and effect relationship has not been established. Priapism has also been reported. Anaphylaxis has rarely been reported.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Should administration of terazosin 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 the renal function should be monitored and supported as needed. Laboratory data indicate that terazosin is highly protein bound; therefore, dialysis may not be of benefit.

Dosage And Administration: Hypertension: The dose and the dosing intervals (12 or 24 hours) should be adjusted to the patient’s individual blood pressure response.

When terazosin is being added to the existing antihypertensive therapy, the patient should be carefully monitored for the occurrence of hypotension. If a diuretic or other antihypertensive agent is being added to the terazosin regimen, dosage reduction of terazosin and retitration with careful monitoring may be necessary. The following is a guide to its administration:

Initial Dose: 1 mg of terazosin at bedtime is the starting dose for all patients and this dose should not be exceeded; compliance with this initial dosage recommendation should be strictly observed to minimize the potential for acute hypotensive episodes.

Subsequent Doses: The dose may be slowly increased to achieve the desired blood pressure response. The usual dose range is 1 to 5 mg once-a-day. Some patients may benefit from doses up to 20 mg/day which is the maximum recommended daily dose.

The blood pressure should be monitored at the end of the dosing interval to assure that control is maintained. It is also helpful to measure the blood pressure 2 to 3 hours after dosing to see if the maximum and minimum responses are similar and to evaluate symptoms.

If response to terazosin is substantially diminished at 24 hours, patients may be tried on a larger dose or twice daily dosage regimen. The latter should also be considered if adverse effects such as dizziness, palpitations or orthostatic complaints are seen 2 to 3 hours after dosing.

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

Benign Prostatic Hyperplasia (BPH): The dose of terazosin should be adjusted to the patient’s individual response.

Initial Dose: 1 mg of terazosin 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.

Subsequent Doses: The dose should be increased in a stepwise fashion at weekly intervals to 2, 5 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 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 6 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 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 therapy should also be discontinued if terazosin side effects are more bothersome than BPH symptoms or if the patient develops a urinary complication while on terazosin therapy.

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

Availability And Storage: 1 mg: 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. Bottles of 100.

2 mg: 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. Bottles of 100.

5 mg: 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. Bottles of 100.

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

Starter Pack: 1 strip (7) of each 1 mg and 2 mg tablets and 2 strips (2´7) of 5 mg tablets in blisters.

Store tablets at controlled room temperature (15 to 30°C). (Shown in Product Recognition Section)

HYTRIN® Abbott Terazosin HCl Antihypertensive – Symptomatic Treatment of Benign Prostatic Hyperplasia (BPH)

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