The signs and symptoms of orthostasis (postural hypotension, dizziness and vertigo) were detected more frequently in FLOMAX capsule-treated patients than in placebo recipients. As with other alpha-adrenergic blocking agents there is a potential risk of syncope (see ADVERSE REACTIONS).
Patients beginning treatment with FLOMAX capsules should be cautioned to avoid situations where injury could result should syncope occur.
Doses of FLOMAX higher than 0.4 mg (e.g., 0.8 mg) should not be used in combination with strong inhibitors of CYP3A4 (e.g., ketoconazole).
Rarely (probably less than 1 in 50,000 patients), tamsulosin, like other alpha1 antagonists, has been associated with priapism (persistent painful penile erection unrelated to sexual activity). Because this condition can lead to permanent impotence if not properly treated, patients must be advised about the seriousness of the condition (see PRECAUTIONS, Information for Patients).
Carcinoma of the Prostate: Carcinoma of the prostate and BPH cause many of the same symptoms. These two diseases frequently co-exist. Patients should be evaluated prior to the start of FLOMAX capsules therapy to rule out the presence of carcinoma of the prostate.
Intraoperative Floppy Iris Syndrome: Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha-1 blockers, including FLOMAX capsules. Most reports were in patients taking the alpha-1 blocker when IFIS occurred, but in some cases, the alpha-1 blocker had been stopped prior to surgery. In most of these cases, the alpha-1-blocker had been stopped recently prior to surgery (2 to 14 days), but in a few cases, IFIS was reported after the patient had been off the alpha-1 blocker for a longer period (5 weeks to 9 months). IFIS is a variant of small pupil syndrome and 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. The benefit of stopping alpha-1 blocker therapy prior to cataract surgery has not been established.
Sulfa Allergy: In patients with sulfa allergy, allergic reaction to Flomax® (tamsulosin hydrochloride) capsules has been rarely reported. If a patient reports a serious or life-threatening sulfa allergy, caution is warranted when administering FLOMAX capsules.
Drug-Drug Interactions: The pharmacokinetic and pharmacodynamic interactions between FLOMAX capsules and other alpha-adrenergic blocking agents have not been determined. However, interactions may be expected and FLOMAX capsules should NOT be used in combination with other alpha-adrenergic blocking agents.
The pharmacokinetic interaction between cimetidine, a mild inhibitor of several CYP enzymes, and FLOMAX capsules was investigated in 10 subjects (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions ). The results indicate significant changes in both tamsulosin hydrochloride clearance (26% decrease) and exposure (44% increase in AUC). Therefore, FLOMAX capsules should be used with caution in combination with cimetidine, particularly at doses higher than 0.4 mg.
Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6. When co-administered with 0.4 mg FLOMAX capsules, ketoconazole (a strong CYP3A4 inhibitor) caused an increase in the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. FLOMAX capsules 0.4 mg should therefore be used with caution in combination with strong inhibitors of CYP3A4. Daily doses of FLOMAX higher than 0.4 mg (e.g., 0.8 mg) should not be used in combination with strong inhibitors of CYP3A4 (see WARNINGS).When co-administered with 0.4 mg FLOMAX capsules, paroxetine (a strong CYP2D6 inhibitor) caused an increase in the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively. FLOMAX capsules should therefore be used with caution in combination with strong inhibitors of CYP2D6, particularly at doses higher than 0.4 mg (e.g., 0.8 mg).
Results from limited in vitro and in vivo drug-drug interaction studies between tamsulosin hydrochloride and warfarin are inconclusive. Therefore, caution should be exercised with concomitant administration of warfarin and FLOMAX capsules.
See also Drug-Drug Interactions studies in CLINICAL PHARMACOLOGY, Pharmacokinetics subsection.
Information for Patients (see PATIENT INFORMATION)
Patients should be told about the possible occurrence of symptoms related to postural hypotension, such as dizziness, when taking FLOMAX capsules, and they should be cautioned about driving, operating machinery or performing hazardous tasks.
Patients should be advised not to crush, chew or open the FLOMAX capsules.
Patients should be advised about the possibility of priapism as a result of treatment with FLOMAX capsules and other similar medications. Patients should be informed that this reaction is extremely rare, but if not brought to immediate medical attention, can lead to permanent erectile dysfunction (impotence).
Patients should be advised that if they are considering cataract surgery, to tell their ophthalmologist that they have taken Flomax® (tamsulosin hydrochloride) capsules.
No laboratory test interactions with FLOMAX capsules are known. Treatment with FLOMAX capsules for up to 12 months had no significant effect on prostate-specific antigen (PSA).
Teratogenic Effects, Pregnancy Category B.
Administration of tamsulosin hydrochloride to pregnant female rats at dose levels up to 300 mg/kg/day (approximately 50 times the human therapeutic AUC exposure) revealed no evidence of harm to the fetus. Administration of tamsulosin hydrochloride to pregnant rabbits at dose levels up to 50 mg/kg/day produced no evidence of fetal harm. FLOMAX capsules are not indicated for use in women.
Of the total number of subjects (1783) in clinical studies of tamsulosin, 36% were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and the other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations , Geriatrics (Age)) .
FLOMAX capsules are not indicated for use in women.
FLOMAX capsules are not indicated for use in pediatric populations.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Rats administered doses up to 43 mg/kg/day in males and 52 mg/kg/day in females had no increases in tumor incidence, with the exception of a modest increase in the frequency of mammary gland fibroadenomas in female rats receiving doses ≥5.4 mg/kg (P <0.015). The highest doses of tamsulosin hydrochloride evaluated in the rat carcinogenicity study produced systemic exposures (AUC) in rats 3 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/day.
Mice were administered doses up to 127 mg/kg/day in males and 158 mg/kg/day in females. There were no significant tumor findings in male mice. Female mice treated for 2 years with the two highest doses of 45 and 158 mg/kg/day had statistically significant increases in the incidence of mammary gland fibroadenomas (P<0.0001) and adenocarcinomas (P<0.0075). The highest dose levels of tamsulosin hydrochloride evaluated in the mice carcinogenicity study produced systemic exposures (AUC) in mice 8 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/day.
The increased incidences of mammary gland neoplasms in female rats and mice were considered secondary to tamsulosin hydrochloride-induced hyperprolactinemia. It is not known if Flomax® (tamsulosin hydrochloride) capsules elevate prolactin in humans. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is not known.
Tamsulosin hydrochloride produced no evidence of mutagenic potential in vitro in the Ames reverse mutation test, mouse lymphoma thymidine kinase assay, unscheduled DNA repair synthesis assay, and chromosomal aberration assays in Chinese hamster ovary cells or human lymphocytes. There were no mutagenic effects in the in vivo sister chromatid exchange and mouse micronucleus assay.
Studies in rats revealed significantly reduced fertility in males dosed with single or multiple daily doses of 300 mg/kg/day of tamsulosin hydrochloride (AUC exposure in rats about 50 times the human exposure with the maximum therapeutic dose). The mechanism of decreased fertility in male rats is considered to be an effect of the compound on the vaginal plug formation possibly due to changes of semen content or impairment of ejaculation. The effects on fertility were reversible showing improvement by 3 days after a single dose and 4 weeks after multiple dosing. Effects on fertility in males were completely reversed within nine weeks of discontinuation of multiple dosing. Multiple doses of 10 and 100 mg/kg/day tamsulosin hydrochloride (1/5 and 16 times the anticipated human AUC exposure) did not significantly alter fertility in male rats. Effects of tamsulosin hydrochloride on sperm counts or sperm function have not been evaluated.
Studies in female rats revealed significant reductions in fertility after single or multiple dosing with 300 mg/kg/day of the R-isomer or racemic mixture of tamsulosin hydrochloride, respectively. In female rats, the reductions in fertility after single doses were considered to be associated with impairments in fertilization. Multiple dosing with 10 or 100 mg/kg/day of the racemic mixture did not significantly alter fertility in female rats.