Uroxatral Warnings, Precautions, Pregnancy, Nursing, Abuse - Alfuzosin HCl

Uroxatral Warnings, Precautions, Pregnancy, Nursing, Abuse - Alfuzosin HCl

WARNINGS

Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of UROXATRAL (alfuzosin HCl extended-release tablets). As with other alpha-blockers, there is a potential for syncope. Patients should be warned of the possible occurrence of such events and should avoid situations where injury could result should syncope occur. Care should be taken when UROXATRAL is administered to patients with symptomatic hypotension or patients who have had a hypotensive response to other medications.

Prostatic Carcinoma: 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 therapy with UROXATRAL (alfuzosin HCl extended-release tablets) to rule out the presence of carcinoma of the prostate.

Drug-Drug Interactions: The pharmacokinetic and pharmacodynamic interactions between UROXATRAL and other alpha-blockers have not been determined. However, interactions may be expected, and UROXATRAL should NOT be used in combination with other alpha-blockers.

Coronary Insufficiency: If symptoms of angina pectoris should newly appear or worsen, UROXATRAL should be discontinued.

Hepatic Insufficiency: UROXATRAL should not be given to patients with moderate or severe hepatic insufficiency. (See CONTRAINDICATIONS). The pharmacokinetics of UROXATRAL have not been studied in patients with mild hepatic insufficiency (See CLINICAL PHARMACOLOGY, Patients with Hepatic Insufficiency).

Renal Insufficiency: Systemic exposure was increased by approximately 50% in pharmacokinetic studies of patients with mild, moderate, and severe renal insufficiency (See CLINICAL PHARMACOLOGY, Special Populations). In phase 3 studies, the safety profile of patients with mild (n=172) or moderate (n=56) renal impairment was similar to the patients with normal renal function in those studies. Safety data are available in only a limited number of patients (n=6) with creatinine clearance below 30 mL/min; therefore, caution should be exercised when UROXATRAL is administered in patients with severe renal insufficiency.

Patients with Congenital or Acquired QT Prolongation: In a study of QT effect in 45 healthy males (See CLINICAL PHARMACOLOGY, Electrophysiology), the QT effect appeared less with alfuzosin 10 mg than with 40 mg, and the effect of alfuzosin 40 mg did not appear as large as that of the active control moxifloxacin at its therapeutic dose. This observation should be considered in clinical decisions to prescribe UROXATRAL for patients with a known history of QT prolongation or patients who are taking medications known to prolong QT, although there has been no signal of Torsades de Pointe in the extensive post-marketing experience with alfuzosin outside the United States. There are no known PK/PD studies of the effects of other alpha blockers on cardiac repolarization.

INFORMATION FOR PATIENTS

Patients should be told about the possible occurrence of symptoms related to postural hypotension, such as dizziness, when beginning UROXATRAL, and they should be cautioned about driving, operating machinery, or performing hazardous tasks during this period.

UROXATRAL should be taken with food and with the same meal each day.

Patients should be advised not to crush or chew UROXATRAL tablets.

No laboratory test interactions with UROXATRAL tablets are known.

UROXATRAL is not indicated for use in children.

Of the total number of subjects in clinical studies of UROXATRAL, 48% were 65 years of age and over, whereas 11% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. (See CLINICAL PHARMACOLOGY, Elderly subsection.)

There was no evidence of a drug-related increase in the incidence of tumors in mice following dietary administration of 100 mg/kg/day alfuzosin for 98 weeks (13 and 15 times the level of exposure to humans based on AUC of unbound drug) in females and males, respectively. The highest dose tested in female mice may not have constituted a maximally tolerated dose. Likewise, there was no evidence of a drug-related increase in the incidence of tumors in rats following dietary administration of 100 mg/kg/day alfuzosin for 104 weeks (53 and 37 times the level of exposure to humans based on AUC of unbound drug) in females and males, respectively.

Alfuzosin showed no evidence of mutagenic effect in the Ames and mouse lymphoma assays, and was free of any clastogenic effects in the Chinese hamster ovary cell and in vivo mouse micronucleus assays. Alfuzosin treatment did not induce DNA repair in a human cell line.

There was no evidence of reproductive organ toxicity when male rats were given alfuzosin at daily oral (gavage) doses of up to 250 mg/kg/day for 26 weeks, which corresponds to levels of exposure several hundred times that in humans. No impairment of fertility was observed following oral (gavage) administration to male rats at doses of up to 125 mg/kg/day for 70 days. Estrous cycling was inhibited in rats and dogs at doses of 25 mg/kg and 20 mg/kg, respectively, corresponding to levels of systemic exposure (based on AUC of unbound drug) 12- and 18-fold higher, respectively, than in humans, although this did not result in impaired fertility in rats.

Teratogenic Effects, Pregnancy and Lactation Category B. UROXATRAL is not indicated for use in women.

There was no evidence of teratogenicity or embryotoxicity in rats at maternal (oral gavage) doses up to 250 mg/kg/day, corresponding to systemic exposure levels 1,200-fold higher than in humans. In rabbits, up to the dose of 100 mg/kg/day (approximately 3 times the clinical dose by body surface area) given orally (via gavage), no evidence of fetal toxicity or teratogenicity was seen.

Gestation was slightly prolonged in rats with a maternal dose >5 mg/kg/day (oral gavage), which corresponds to systemic exposure levels (based on AUC of unbound drug) 12 times higher than human exposure levels, but there were no difficulties with parturition.

UROXATRAL is not indicated for use in women.