Componentes:
Método de ação:
Opção de tratamento:
Medicamente revisado por Kovalenko Svetlana Olegovna, Farmácia Última atualização em 07.04.2022
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Tratamento benigno de hiperplasia prostática (BPH)
Tam-D® As cápsulas (dutasterida e cloridrato de tamsulosina) são indicadas para o tratamento da HBP sintomática em homens com próstata aumentada.
Limitações de uso
Os produtos contendo dutasterida, incluindo Tam-D, não são aprovados para a prevenção do câncer de próstata.
A dose recomendada de Tam-D é de 1 cápsula (0,5 mg de dutasterida e 0,4 mg de cloridrato de tamsulosina), tomada uma vez ao dia aproximadamente 30 minutos após a mesma refeição todos os dias.
As cápsulas devem ser engolidas inteiras e não mastigadas ou abertas. O contato com o conteúdo da cápsula Tam-D pode resultar em irritação da mucosa orofaríngea.
Tam-D está contra-indicado para uso em :
- Gravidez. Nos estudos de reprodução animal e toxicidade no desenvolvimento, a dutasterida inibiu o desenvolvimento da genitália externa do feto masculino. Portanto, Tam-D pode causar danos fetais quando administrado a uma mulher grávida. Se Tam-D for utilizado durante a gravidez ou se a paciente engravidar enquanto estiver a tomar Tam-D, deve ser informado o risco potencial para o feto.
- Mulheres com potencial para engravidar.
- Pacientes pediátricos.
- Pacientes com hipersensibilidade clinicamente significativa demonstrada anteriormente (por exemplo,., reações cutâneas graves, angioedema, urticária, prurido, sintomas respiratórios) à dutasterida, outros inibidores da 5alfa-redutase, tamsulosina ou qualquer outro componente da Tam-D
WARNINGS
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS
Orthostatic Hypotension
As with other alpha-adrenergic antagonists, orthostatic hypotension (postural hypotension, dizziness, and vertigo) may occur in patients treated with tamsulosin-containing products, including Tam-D, and can result in syncope. Patients starting treatment with Tam-D should be cautioned to avoid situations where syncope could result in an injury.
Drug-Drug Interactions
Strong Inhibitors Of CYP3A4
Tamsulosin-containing products, including Tam-D, should not be coadministered with strong CYP3A4 inhibitors (e.g., ketoconazole) as this can significantly increase tamsulosin exposure.
Moderate Inhibitors Of CYP3A4, Inhibitors Of CYP2D6, Or A Combination Of Both CYP3A4 And CYP2D6 Inhibitors
Tamsulosin-containing products, including Tam-D, should be used with caution when coadministered with moderate inhibitors of CYP3A4 (e.g., erythromycin), strong (e.g., paroxetine) or moderate (e.g., terbinafine) inhibitors of CYP2D6, a combination of both CYP3A4 and CYP2D6 inhibitors, or in patients known to be poor metabolizers of CYP2D6, as there is a potential for significant increase in tamsulosin exposure.
Cimetidine
Caution is advised when tamsulosin-containing products, including Tam-D, are coadministered with cimetidine.
Other Alpha-Adrenergic Antagonists
Tamsulosin-containing products, including Tam-D, should not be coadministered with other alpha-adrenergic antagonists because of the increased risk of symptomatic hypotension.
Phosphodiesterase-5 (PDE-5) Inhibitors
Caution is advised when alpha-adrenergic-antagonist-containing products, including Tam-D, are coadministered with PDE-5 inhibitors. Alpha-adrenergic antagonists and PDE-5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these 2 drug classes can potentially cause symptomatic hypotension.
Warfarin
Caution should be exercised with concomitant administration of warfarin and tamsulosincontaining products, including Tam-D.
Effects On Prostate-Specific Antigen (PSA) And The Use Of PSA In Prostate Cancer Detection
Coadministration of dutasteride with tamsulosin resulted in similar changes to serum PSA as with dutasteride monotherapy.
In clinical trials, dutasteride reduced serum PSA concentration by approximately 50% within 3 to 6 months of treatment. This decrease was predictable over the entire range of PSA values in patients with symptomatic BPH, although it may vary in individuals. Dutasteride-containing treatment, including Tam-D, may also cause decreases in serum PSA in the presence of prostate cancer. To interpret serial PSAs in men treated with a dutasteride-containing product, including Tam-D, a new baseline PSA should be established at least 3 months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on a dutasteride-containing treatment, including Tam-D, may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5-alpha-reductase inhibitor. Noncompliance with Tam-D may also affect PSA test results.
To interpret an isolated PSA value in a man treated with Tam-D, for 3 months or more, the PSA value should be doubled for comparison with normal values in untreated men.
The free-to-total PSA ratio (percent free PSA) remains constant, even under the influence of dutasteride. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving Tam-D, no adjustment to its value appears necessary.
Increased Risk Of High-Grade Prostate Cancer
In men aged 50 to 75 years with a prior negative biopsy for prostate cancer and a baseline PSA between 2.5 ng/mL and 10.0 ng/mL taking dutasteride in the 4-year Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, there was an increased incidence of Gleason score 8 to 10 prostate cancer compared with men taking placebo (dutasteride 1.0% versus placebo 0.5%). In a 7-year placebo-controlled clinical trial with another 5-alpha-reductase inhibitor (finasteride 5 mg, PROSCAR®), similar results for Gleason score 8 to 10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%).
5-alpha-reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5-alpha-reductase inhibitors to reduce prostate volume or trial-related factors impacted the results of these trials has not been established.
Evaluation For Other Urological Diseases
Prior to initiating treatment with Tam-D, consideration should be given to other urological conditions that may cause similar symptoms. In addition, BPH and prostate cancer may coexist.
Exposure Of Women–Risk To Male Fetus
Tam-D capsules should not be handled by a woman who is pregnant or who could become pregnant. Dutasteride is absorbed through the skin and could result in unintended fetal exposure. If a woman who is pregnant or could become pregnant comes in contact with a leaking capsule, the contact area should be washed immediately with soap and water.
Priapism
Priapism (persistent painful penile erection unrelated to sexual activity) has been associated (probably less than 1 in 50,000) with the use of alpha-adrenergic antagonists, including tamsulosin, which is a component of Tam-D. Because this condition can lead to permanent impotence if not properly treated, patients should be advised about the seriousness of the condition.
Blood Donation
Men being treated with a dutasteride-containing product, including Tam-D, should not donate blood until at least 6 months have passed following their last dose. The purpose of this deferred period is to prevent administration of dutasteride to a pregnant female transfusion recipient.
Intraoperative Floppy Iris Syndrome
Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract and glaucoma surgery in some patients on or previously treated with alpha-adrenergic antagonists, including tamsulosin, which is a component of Tam-D.
Most reports were in patients taking the alpha-adrenergic antagonist when IFIS occurred, but in some cases, the alpha-adrenergic antagonist had been stopped prior to surgery. In most of these cases, the alpha-adrenergic antagonist had been stopped recently prior to surgery (2 to 14 days), but in a few cases, IFIS was reported after the patients had been off the alpha-adrenergic antagonist 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.
IFIS may increase the risk of eye complications during and after the operation. The benefit of stopping alpha-adrenergic antagonist therapy prior to cataract or glaucoma surgery has not been established. The initiation of therapy with tamsulosin in patients for whom cataract or glaucoma surgery is scheduled is not recommended.
Sulfa Allergy
In patients with sulfa allergy, allergic reaction to tamsulosin has been rarely reported. If a patient reports a serious or life-threatening sulfa allergy, caution is warranted when administering tamsulosin-containing products, including Tam-D.
Effect On Semen Characteristics
Dutasteride
The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in normal volunteers aged 18 to 52 (n = 27 dutasteride, n = 23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, the mean percent reductions from baseline in total sperm count, semen volume, and sperm motility were 23%, 26%, and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group. Sperm concentration and sperm morphology were unaffected. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23% lower than baseline. While mean values for all semen parameters at all time-points remained within the normal ranges and did not meet predefined criteria for a clinically significant change (30%), 2 subjects in the dutasteride group had decreases in sperm count of greater than 90% from baseline at 52 weeks, with partial recovery at the 24-week follow-up. The clinical significance of dutasteride’s effect on semen characteristics for an individual patient’s fertility is not known.
Tamsulosin
The effects of tamsulosin hydrochloride on sperm counts or sperm function have not been evaluated.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Orthostatic Hypotension
Inform patients about the possible occurrence of symptoms related to orthostatic hypotension, such as dizziness and vertigo, and the potential risk of syncope when taking Tam-D. Caution patients starting treatment with Tam-D to avoid situations where injury could result should syncope occur (e.g., driving, operating machinery, performing hazardous tasks). Advise patients to sit or lie down at the first signs of orthostatic hypotension.
Drug Interactions
Advise patients that Tam-D should not be used in combination with strong inhibitors of CYP3A4.
PSA Monitoring
Inform patients that Tam-D reduces serum PSA levels by approximately 50% within 3 to 6 months of therapy, although it may vary for each individual. For patients undergoing PSA screening, increases in PSA levels while on treatment with Tam-D may signal the presence of prostate cancer and should be evaluated by a healthcare provider.
Risk Of High-Grade Prostate Cancer
Inform patients that there was an increase in high-grade prostate cancer in men treated with 5alpha-reductase inhibitors (which are indicated for BPH treatment), including dutasteride, which is a component of Tam-D, compared with those treated with placebo in trials looking at the use of these drugs to reduce the risk of prostate cancer.
Exposure Of Women–Risk To Male Fetus
Inform patients that Tam-D capsules should not be handled by a woman who is pregnant or who could become pregnant because of the potential for absorption of dutasteride and the subsequent potential risk to a developing male fetus. Dutasteride is absorbed through the skin and could result in unintended fetal exposure. If a pregnant woman or woman of childbearing potential comes in contact with leaking Tam-D capsules, the contact area should be washed immediately with soap and water.
Instructions For Use
Tam-D capsules should be swallowed whole and not chewed, crushed, or opened. Tam-D capsules may become deformed and/or discolored if kept at high temperatures. If this occurs, capsules should not be used.
Priapism
Inform patients about the possibility of priapism as a result of treatment with Tam-D or other alpha-adrenergic–antagonist-containing medications. Inform patients that this reaction is extremely rare, but can lead to permanent erectile dysfunction if not brought to immediate medical attention.
Blood Donation
Inform men treated with Tam-D that they should not donate blood until at least 6 months following their last dose to prevent pregnant women from receiving dutasteride through blood transfusion. Serum levels of dutasteride are detectable for 4 to 6 months after treatment ends.
Intraoperative Floppy Iris Syndrome (IFIS)
Advise patients considering cataract or glaucoma surgery to tell their ophthalmologist that they take or have taken Tam-D, an alpha adrenergic antagonist-containing product.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No non-clinical studies have been conducted with Tam-D. The following information is based on studies performed with dutasteride or tamsulosin.
Carcinogenesis
Dutasteride
A 2-year carcinogenicity study was conducted in B6C3F1 mice at doses of 3, 35, 250, and 500 mg/kg/day for males and 3, 35, and 250 mg/kg/day for females; an increased incidence of benign hepatocellular adenomas was noted at 250 mg/kg/day (290-fold the MRHD of a 0.5-mg daily dose) in female mice only. Two of the 3 major human metabolites have been detected in mice. The exposure to these metabolites in mice is either lower than in humans or is not known.
In a 2-year carcinogenicity study in Han Wistar rats, at doses of 1.5, 7.5, and 53 mg/kg/day in males and 0.8, 6.3, and 15 mg/kg/day in females, there was an increase in Leydig cell adenomas in the testes at 135-fold the MRHD (53 mg/kg/day and greater). An increased incidence of Leydig cell hyperplasia was present at 52-fold the MRHD (male rat doses of 7.5 mg/kg/day and greater). A positive correlation between proliferative changes in the Leydig cells and an increase in circulating luteinizing hormone levels has been demonstrated with 5-alpha-reductase inhibitors and is consistent with an effect on the hypothalamic-pituitary-testicular axis following 5-alpha-reductase inhibition. At tumorigenic doses, luteinizing hormone levels in rats were increased by 167%. In this study, the major human metabolites were tested for carcinogenicity at approximately 1 to 3 times the expected clinical exposure.
Tamsulosin
In a rat carcinogenicity assay, no increases in tumor incidence was observed in rats administered up to 3 times the MRHD of 0.8 mg/day (based on AUC of animal doses up to 43 mg/kg/day in males and up to 52 mg/kg/day in females), with the exception of a modest increase in the frequency of mammary gland fibroadenomas in female rats receiving doses of 5.4 mg/kg or greater.
In a carcinogenicity assay, mice were administered up to 8 times the MRHD of tamsulosin (oral 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 2 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.
The increased incidences of mammary gland neoplasms in female rats and mice were considered secondary to tamsulosin-induced hyperprolactinemia. It is not known if tamsulosin elevates prolactin in humans. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is not known.
Mutagenesis
Dutasteride
Dutasteride was tested for genotoxicity in a bacterial mutagenesis assay (Ames test), a chromosomal aberration assay in Chinese hamster ovary (CHO) cells, and a micronucleus assay in rats. The results did not indicate any genotoxic potential of the parent drug. Two major human metabolites were also negative in either the Ames test or an abbreviated Ames test.
Tamsulosin
Tamsulosin 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 CHO cells or human lymphocytes. There were no mutagenic effects in the in vivo sister chromatid exchange and mouse micronucleus assay.
Impairment Of Fertility
Dutasteride
Treatment of sexually mature male rats with dutasteride at 0.1-to 110-fold the MRHD (animal doses of 0.05, 10, 50, and 500 mg/kg/day for up to 31 weeks) resulted in dose-and time-dependent decreases in fertility; reduced cauda epididymal (absolute) sperm counts but not sperm concentration (at 50 and 500 mg/kg/day); reduced weights of the epididymis, prostate, and seminal vesicles; and microscopic changes in the male reproductive organs. The fertility effects were reversed by recovery week 6 at all doses, and sperm counts were normal at the end of a 14-week recovery period. The 5-alpha-reductase.related changes consisted of cytoplasmic vacuolation of tubular epithelium in the epididymides and decreased cytoplasmic content of epithelium, consistent with decreased secretory activity in the prostate and seminal vesicles. The microscopic changes were no longer present at recovery week 14 in the low-dose group and were partly recovered in the remaining treatment groups. Low levels of dutasteride (0.6 to 17 ng/mL) were detected in the serum of untreated female rats mated to males dosed at 10, 50, or 500 mg/kg/day for 29 to 30 weeks.
In a fertility study in female rats, oral administration of dutasteride at doses of 0.05, 2.5, 12.5, and 30 mg/kg/day resulted in reduced litter size, increased embryo resorption and feminization of male fetuses (decreased anogenital distance) at 2-to 10-fold the MRHD (animal doses of 2.5 mg/kg/day or greater). Fetal body weights were also reduced at less than 0.02-fold the MRHD in rats (0.5 mg/kg/day).
Tamsulosin
Studies in rats revealed significantly reduced fertility in males at approximately 50 times the MRHD based on AUC (single or multiple daily doses of 300 mg/kg/day of tamsulosin hydrochloride). 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 0.2 and 16 times the MRHD (animal doses of 10 and 100 mg/kg/day tamsulosin hydrochloride) did not significantly alter fertility in male rats. Effects of tamsulosin 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.
Estimates of exposure multiples comparing animal studies with the MRHD for dutasteride are based on clinical serum concentration at steady state.
Estimates of exposure multiples comparing animal studies with the MRHD for tamsulosin are based on AUC.
Use In Specific Populations
Pregnancy
Pregnancy Category X. There are no adequate and well-controlled studies in pregnant women with Tam-D or its individual components.
Dutasteride
Dutasteride is contraindicated for use in women of childbearing potential and during pregnancy. Dutasteride is a 5-alpha-reductase inhibitor that prevents conversion of testosterone to dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia. In animal reproduction and developmental toxicity studies, dutasteride inhibited normal development of external genitalia in male fetuses. Therefore, dutasteride may cause fetal harm when administered to a pregnant woman. If dutasteride is used during pregnancy or if the patient becomes pregnant while taking dutasteride, the patient should be apprised of the potential hazard to the fetus.
In an embryo-fetal development study in female rats, oral administration of dutasteride at doses 10 times less than the maximum recommended human dose (MRHD) of 0.5 mg daily resulted in abnormalities of male genitalia in the fetus (decreased anogenital distance at 0.05 mg/kg/day), nipple development, hypospadias, and distended preputial glands in male offspring (at all doses of 0.05, 2.5, 12.5, and 30 mg/kg/day). An increase in stillborn pups was observed at 111 times the MRHD, and reduced fetal body weight was observed at doses of about 15 times the MRHD (animal dose of 2.5 mg/kg/day). Increased incidences of skeletal variations considered to be delays in ossification associated with reduced body weight were observed at doses at about 56 times the MRHD (animal dose of 12.5 mg/kg/day).
In a rabbit embryo-fetal study, doses 28-to 93-fold the MRHD (animal doses of 30, 100, and 200 mg/kg/day) were administered orally during the period of major organogenesis (gestation days 7 to 29) to encompass the late period of external genitalia development. Histological evaluation of the genital papilla of fetuses revealed evidence of feminization of the male fetus at all doses. A second embryo-fetal study in rabbits at 0.3-to 53-fold the expected clinical exposure (animal doses of 0.05, 0.4, 3.0, and 30 mg/kg/day) also produced evidence of feminization of the genitalia in male fetuses at all doses.
In an oral pre-and post-natal development study in rats, dutasteride doses of 0.05, 2.5, 12.5, or 30 mg/kg/day were administered. Unequivocal evidence of feminization of the genitalia (i.e., decreased anogenital distance, increased incidence of hypospadias, nipple development) of male offspring occurred at 14-to 90-fold the MRHD (animal doses of 2.5 mg/kg/day or greater). At 0.05-fold the expected clinical exposure (animal dose of 0.05 mg/kg/day), evidence of feminization was limited to a small, but statistically significant, decrease in anogenital distance. Animal doses of 2.5 to 30 mg/kg/day resulted in prolonged gestation in the parental females and a decrease in time to vaginal patency for female offspring and a decrease in prostate and seminal vesicle weights in male offspring. Effects on newborn startle response were noted at doses greater than or equal to 12.5 mg/kg/day. Increased stillbirths were noted at 30 mg/kg/day.
In an embryo-fetal development study, pregnant rhesus monkeys were exposed intravenously to a dutasteride blood level comparable to the dutasteride concentration found in human semen. Dutasteride was administered on gestation days 20 to 100 at doses of 400, 780, 1,325, or 2,010 ng/day (12 monkeys/group). The development of male external genitalia of monkey offspring was not adversely affected. Reduction of fetal adrenal weights, reduction in fetal prostate weights, and increases in fetal ovarian and testis weights were observed at the highest dose tested in monkeys. Based on the highest measured semen concentration of dutasteride in treated men (14 ng/mL), these doses represent 0.8 to 16 times the potential maximum exposure of a 50-kg human female to 5 mL semen daily from a dutasteride-treated man, assuming 100% absorption. (These calculations are based on blood levels of parent drug which are achieved at 32 to 186 times the daily doses administered to pregnant monkeys on a ng/kg basis). Dutasteride is highly bound to proteins in human semen (greater than 96%), potentially reducing the amount of dutasteride available for vaginal absorption. It is not known whether rabbits or rhesus monkeys produce any of the major human metabolites.
Estimates of exposure multiples comparing animal studies to the MRHD for dutasteride are based on clinical serum concentration at steady state.
Tamsulosin
Administration of tamsulosin to pregnant female rats at dose levels up to approximately 50 times the human therapeutic AUC exposure (animal dose of 300 mg/kg/day) 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. However, because of the effect of dutasteride on the fetus, Tam-D is contraindicated for use in pregnant women. Estimates of exposure multiples comparing animal studies to the MRHD for tamsulosin are based on AUC.
Nursing Mothers
Tam-D is contraindicated for use in women of childbearing potential, including nursing women. It is not known whether dutasteride or tamsulosin is excreted in human milk.
Pediatric Use
Tam-D is contraindicated for use in pediatric patients. Safety and effectiveness of Tam-D in pediatric patients have not been established.
Geriatric Use
Of 1,610 male subjects treated with coadministered dutasteride and tamsulosin in the CombAT trial, 58% of enrolled subjects were aged 65 years and older and 13% of enrolled subjects were aged 75 years and older. No overall differences in safety or efficacy were observed between these subjects and younger subjects but greater sensitivity of some older individuals cannot be ruled out.
Renal Impairment
The effect of renal impairment on dutasteride and tamsulosin pharmacokinetics has not been studied using Tam-D. Because no dosage adjustment is necessary for dutasteride or tamsulosin in patients with moderate-to-severe renal impairment (10≤ CLcr <30 mL/min/1.73 m2), no dosage adjustment is necessary for Tam-D in patients with moderate-to-severe renal impairment. However, patients with end-stage renal disease (CLcr<10 mL/min/1.73 m2) have not been studied.
Hepatic Impairment
The effect of hepatic impairment on dutasteride and tamsulosin pharmacokinetics has not been studied using Tam-D. The following text reflects information available for the individual components.
Dutasteride
The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients. However, in a clinical trial where 60 subjects received 5 mg (10 times the therapeutic dose) daily for 24 weeks, no additional adverse events were observed compared with those observed at the therapeutic dose of 0.5 mg.
Tamsulosin
Patients with moderate hepatic impairment do not require an adjustment in tamsulosin dosage. Tamsulosin has not been studied in patients with severe hepatic impairment.
Clinical Trials Experience
The clinical efficacy and safety of coadministered dutasteride and tamsulosin, which are individual components of Tam-D, have been evaluated in a multicenter, randomized, double-blind, parallel group trial (the Combination with Alpha-Blocker Therapy, or CombAT, trial). Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trial of another drug and may not reflect the rates observed in practice.
- The most common adverse reactions reported in subjects receiving coadministered dutasteride and tamsulosin were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disorders, and dizziness. Ejaculation disorders occurred significantly more in subjects receiving coadministration therapy (11%) compared with those receiving dutasteride (2%) or tamsulosin (4%) as monotherapy.
- Trial withdrawal due to adverse reactions occurred in 6% of subjects receiving coadministered dutasteride and tamsulosin and in 4% of subjects receiving dutasteride or tamsulosin as monotherapy. The most common adverse reaction in all treatment arms leading to trial withdrawal was erectile dysfunction (1% to 1.5%).
In the CombAT trial, over 4,800 male subjects with BPH were randomly assigned to receive 0.5 mg dutasteride, 0.4 mg tamsulosin hydrochloride, or coadministration therapy (0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride) administered once daily in a 4-year double-blind trial. Overall, 1,623 subjects received monotherapy with dutasteride; 1,611 subjects received monotherapy with tamsulosin; and 1,610 subjects received coadministration therapy. The population was aged 49 to 88 years (mean age: 66 years) and 88% were white. Table 1 summarizes adverse reactions reported in at least 1% of subjects receiving coadministration therapy and at a higher incidence than subjects receiving either dutasteride or tamsulosin as monotherapy.
Table 1. Adverse Reactions Reported over a 48-Month Period in ≥1% of Subjects and More Frequently in the Coadministration Therapy Group than the Dutasteride or Tamsulosin Monotherapy Group (CombAT) by Time of Onset
Adverse Reaction | Adverse Reaction Time of Onset | ||||
Year 1 | Year 2 | Year 3 | Year 4 | ||
Months 0-6 | Months 7-12 | ||||
Coadministrationa | (n = 1,610) | (n = 1,527) | (n = 1,428) | (n = 1,283) | (n = 1,200) |
Dutasteride | (n = 1,623) | (n = 1,548) | (n = 1,464) | (n = 1,325) | (n = 1,200) |
Tamsulosin | (n = 1,611) | (n = 1,545) | (n = 1,468) | (n = 1,281) | (n = 1,112) |
Ejaculation disordersb,c | |||||
Coadministration | 7.8% | 1.6% | 1.0% | 0.5% | <0.1% |
Dutasteride | 1.0% | 0.5% | 0.5% | 0.2% | 0.3% |
Tamsulosin | 2.2% | 0.5% | 0.5% | 0.2% | 0.3% |
Impotencec,d | |||||
Coadministration | 5.4% | 1.1% | 1.8% | 0.9% | 0.4% |
Dutasteride | 4.0% | 1.1% | 1.6% | 0.6% | 0.3% |
Tamsulosin | 2.6% | 0.8% | 1.0% | 0.6% | 1.1% |
Decreased libidoc,e | |||||
Coadministration | 4.5% | 0.9% | 0.8% | 0.2% | 0.0% |
Dutasteride | 3.1% | 0.7% | 1.0% | 0.2% | 0.0% |
Tamsulosin | 2.0% | 0.6% | 0.7% | 0.2% | <0.1% |
Breast disordersf | |||||
Coadministration | 1.1% | 1.1% | 0.8% | 0.9% | 0.6% |
Dutasteride | 0.9% | 0.9% | 1.2% | 0.5% | 0.7% |
Tamsulosin | 0.4% | 0.4% | 0.4% | 0.2% | 0.0% |
Dizziness | |||||
Coadministration | 1.1% | 0.4% | 0.1% | <0.1% | 0.2% |
Dutasteride | 0.5% | 0.3% | 0.1% | <0.1% | <0.1% |
Tamsulosin | 0.9% | 0.5% | 0.4% | <0.1% | 0.0% |
a Coadministration = AVODART® 0.5 mg once daily plus tamsulosin 0.4 mg once daily. b Includes anorgasmia, retrograde ejaculation, semen volume decreased, orgasmic sensation decreased, orgasm abnormal, ejaculation delayed, ejaculation disorder, ejaculation failure, and premature ejaculation. c These sexual adverse reactions are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse reactions may persist after treatment discontinuation. The role of dutasteride in this persistence is unknown. d Includes erectile dysfunction and disturbance in sexual arousal. e Includes libido decreased, libido disorder, loss of libido, sexual dysfunction, and male sexual dysfunction. f Includes breast enlargement, gynecomastia, breast swelling, breast pain, breast tenderness, nipple pain, and nipple swelling. |
Cardiac Failure
In CombAT, after 4 years of treatment, the incidence of the composite term cardiac failure in the coadministration group (12/1,610; 0.7%) was higher than in either monotherapy group: dutasteride, 2/1,623 (0.1%) and tamsulosin, 9/1,611 (0.6%). Composite cardiac failure was also examined in a separate 4-year placebo-controlled trial evaluating dutasteride in men at risk for development of prostate cancer. The incidence of cardiac failure in subjects taking dutasteride was 0.6% (26/4,105) compared with 0.4% (15/4,126) in subjects on placebo. A majority of subjects with cardiac failure in both trials had comorbidities associated with an increased risk of cardiac failure. Therefore, the clinical significance of the numerical imbalances in cardiac failure is unknown. No causal relationship between dutasteride alone or coadministered with tamsulosin and cardiac failure has been established. No imbalance was observed in the incidence of overall cardiovascular adverse events in either trial.
Additional information regarding adverse reactions in placebo-controlled trials with dutasteride or tamsulosin monotherapy follows.
Dutasteride
Long-term Treatment (Up to 4 Years)
High-grade Prostate Cancer: The REDUCE trial was a randomized, double-blind, placebo-controlled trial that enrolled 8,231 men aged 50 to 75 years with a serum PSA of 2.5 ng/mL to 10 ng/mL and a negative prostate biopsy within the previous 6 months. Subjects were randomized to receive placebo (n = 4,126) or 0.5-mg daily doses of dutasteride (n = 4,105) for up to 4 years. The mean age was 63 years and 91% were white. Subjects underwent protocol-mandated scheduled prostate biopsies at 2 and 4 years of treatment or had “for-cause biopsies” at non-scheduled times if clinically indicated. There was a higher incidence of Gleason score 8 to 10 prostate cancer in men receiving dutasteride (1.0%) compared with men on placebo (0.5%). In a 7-year placebo-controlled clinical trial with another 5-alpha-reductase inhibitor (finasteride 5 mg, PROSCAR), similar results for Gleason score 8 to 10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%).
No clinical benefit has been demonstrated in patients with prostate cancer treated with dutasteride.
Reproductive And Breast Disorders
In the 3 pivotal placebo-controlled BPH trials with dutasteride, each 4 years in duration, there was no evidence of increased sexual adverse reactions (impotence, decreased libido, and ejaculation disorder) or breast disorders with increased duration of treatment. Among these 3 trials, there was 1 case of breast cancer in the dutasteride group and 1 case in the placebo group. No cases of breast cancer were reported in any treatment group in the 4-year CombAT trial or the 4-year REDUCE trial.
The relationship between long-term use of dutasteride and male breast neoplasia is currently unknown.
Tamsulosin
According to the tamsulosin prescribing information, in two 13-week treatment trials with tamsulosin monotherapy, adverse reactions occurring in at least 2% of subjects receiving 0.4 mg tamsulosin hydrochloride and at an incidence higher than in subjects receiving placebo were: infection, asthenia, back pain, chest pain, somnolence, insomnia, rhinitis, pharyngitis, cough increased, sinusitis, and diarrhea.
Signs and Symptoms of Orthostasis
According to the tamsulosin prescribing information, in clinical trials with tamsulosin monotherapy, a positive orthostatic test result was observed in 16% (81/502) of subjects receiving 0.4 mg tamsulosin hydrochloride versus 11% (54/493) of subjects receiving placebo. Because orthostasis was detected more frequently in the tamsulosin-treated subjects than in placebo recipients, there is a potential risk of syncope.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of the individual components of Tam-D. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to drug exposure.
Dutasteride
Immune System Disorders: Hypersensitivity reactions, including rash, pruritus, urticaria, localized edema, serious skin reactions, and angioedema.
Neoplasms: Male breast cancer.
Psychiatric Disorders: Depressed mood.
Reproductive System and Breast Disorders: Testicular pain and testicular swelling.
Tamsulosin
Immune System Disorders: Hypersensitivity reactions, including rash, urticaria, pruritus, angioedema, and respiratory problems have been reported with positive rechallenge in some cases.
Cardiac Disorders: Palpitations, dyspnea, atrial fibrillation, arrhythmia, and tachycardia.
Skin Disorders: Skin desquamation, including Stevens-Johnson syndrome, erythema multiforme, dermatitis exfoliative.
Gastrointestinal Disorders: Constipation, vomiting, dry mouth.
Reproductive System and Breast Disorders: Priapism. Respiratory: Epistaxis.
Vascular Disorders: Hypotension.
Ophthalmologic Disorders: Blurred vision, visual impairment. During cataract and glaucoma surgery, a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome (IFIS) associated with alpha–adrenergic–antagonist therapy.
No data are available with regard to overdosage with Tam-D. The following text reflects information available for the individual components.
Dutasteride
In volunteer trials, single doses of dutasteride up to 40 mg (80 times the therapeutic dose) for 7 days have been administered without significant safety concerns. In a clinical trial, daily doses of 5 mg (10 times the therapeutic dose) were administered to 60 subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 0.5 mg.
There is no specific antidote for dutasteride. Therefore, in cases of suspected overdosage symptomatic and supportive treatment should be given as appropriate, taking the long half-life of dutasteride into consideration.
Tamsulosin
Should overdosage of tamsulosin 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, then administration of intravenous fluids should be considered. If necessary, vasopressors should then be used and renal function should be monitored and supported as needed. Laboratory data indicate that tamsulosin is 94% to 99% protein bound; therefore, dialysis is unlikely to be of benefit.
Dutasterida
Efeito em 5 alfa-di-hidrotestosterona e testosterona
O efeito máximo das doses diárias de dutasterida na redução do DHT depende da dose e é observado dentro de 1 a 2 semanas. Após 1 e 2 semanas de administração diária de dutasterida 0,5 mg, as concentrações séricas médias de DHT foram reduzidas em 85% e 90%, respectivamente. Em pacientes com HBP tratados com dutasterida 0,5 mg / dia por 4 anos, a diminuição média do DHT sérico foi de 94% em 1 ano, 93% em 2 anos e 95% em 3 e 4 anos. O aumento médio da testosterona sérica foi de 19% nos 1 e 2 anos, 26% nos 3 anos e 22% nos 4 anos, mas os níveis médio e mediano permaneceram dentro da faixa fisiológica.
Em pacientes com HBP tratados com 5 mg / dia de dutasterida ou placebo por até 12 semanas antes da ressecção transuretral da próstata, as concentrações médias de DHT no tecido prostático foram significativamente mais baixas no grupo dutasterida em comparação com o placebo (784 e 5.793 pg / g, respectivamenteP<0,001). As concentrações médias de testosterona no tecido prostático foram significativamente maiores no grupo dutasterida em comparação com o placebo (2.073 e 93 pg / g, respectivamente)P<0,001).
Homens adultos com deficiência de 5-alfa-redutase do tipo 2 herdada geneticamente também têm níveis reduzidos de DHT. Esses machos com deficiência de 5-alfa-redutase têm uma pequena próstata ao longo da vida e não desenvolvem HBP. Exceto pelos defeitos urogenitais associados presentes no nascimento, nenhuma outra anormalidade clínica relacionada à deficiência de 5-alfa-redutase foi observada nesses indivíduos.Efeitos em outros hormônios
Em voluntários saudáveis, 52 semanas de tratamento com dutasterida 0,5 mg / dia (n = 26) não resultaram em alterações clinicamente significativas em comparação com o placebo (n = 23) na globulina de ligação ao hormônio sexual, estradiol, hormônio luteinizante, hormônio folículo estimulante, tireoxina (T4 livre) e desidroepiandro. Estatisticamente significantes, foram observados aumentos médios ajustados à linha de base em comparação com o placebo para testosterona total em 8 semanas (97,1 ng / dL) P<0,003) e hormônio estimulador da tireóide às 52 semanas (0,4 mcIU / mL, P<0,05). As variações percentuais medianas da linha de base no grupo dutasterida foram de 17,9% para testosterona em 8 semanas e 12,4% para hormônio estimulador da tireóide em 52 semanas. Depois de parar o dutasterida por 24 semanas, os níveis médios de testosterona e hormônio estimulador da tireóide haviam retornado à linha de base no grupo de indivíduos com dados disponíveis na visita. Em indivíduos com HBP tratados com dutasterida em um grande estudo randomizado, duplo-cego e controlado por placebo, houve um aumento percentual médio no hormônio luteinizante de 12% aos 6 meses e 19% aos 12 e 24 meses.
Outros efeitos
O painel lipídico plasmático e a densidade mineral óssea foram avaliados após 52 semanas de dutasterida 0,5 mg uma vez ao dia em voluntários saudáveis. Não houve alteração na densidade mineral óssea, medida pela absorção de raios-x de energia dupla em comparação com o placebo ou a linha de base. Além disso, o perfil lipídico do plasma (ou seja,., colesterol total, lipoproteínas de baixa densidade, lipoproteínas de alta densidade e triglicerídeos) não foram afetados pela dutasterida. Não foram observadas alterações clinicamente significativas nas respostas dos hormônios adrenais à estimulação do hormônio adrenocorticotrópico (ACTH) em uma população de subconjuntos (n = 13) do estudo voluntário saudável de 1 ano.
A farmacocinética da dutasterida e tamsulosina de Tam-D é comparável à farmacocinética da dutasterida e tamsulosina quando administrada separadamente.
Absorção
Os parâmetros farmacocinéticos da dutasterida e tamsulosina observados após a administração de Tam-D em um estudo cruzado parcial de dose única, randomizado, de 3 períodos, estão resumidos na Tabela 2 abaixo.
Quadro 2. Meios aritméticos (DP) de dutasterida sérica e tamsulosina em parâmetros farmacocinéticos de dose única sob condições de Fed
Componente | N | AUC (0-t) (ng h / mL) | Cmax (ng / mL) | Tmax (h)a | t½ (h) |
Dutasterida | 92 | 39,6 (23,1) | 2.14 (0,77) | 3.00 (1,00-10,00) | |
Tamsulosina | 92 | 187,2 (95,7) | 11.3 (4,44) | 6.00 (2.00-24.00) | 13,5 (3,92)b |
a Mediana (intervalo). b N = 91. |
Dutasterida
Após a administração de uma dose única de 0,5 mg de uma cápsula de gelatina mole, o tempo para atingir o pico da biodisponibilidade absoluta em 5 indivíduos saudáveis é de aproximadamente 60% (variação: 40% a 94%).
Tamsulosina
A absorção de tamsulosina é essencialmente completa (> 90%) após a administração oral de cápsulas de cloridrato de tamsulosina de 0,4 mg em condições de jejum. A tamsulosina exibe cinética linear após doses únicas e múltiplas, com a obtenção de concentrações no estado estacionário até o quinto dia de dosagem uma vez ao dia.
Efeito dos alimentos
Os alimentos não afetam a farmacocinética da dutasterida após a administração de Tam-D. No entanto, foi observada uma diminuição média de 30% na tamsulosina Cmax quando Tam-D foi administrado com alimentos, semelhante ao observado quando a monoterapia com tamsulosina foi administrada em condições de alimentação versus jejum.
Distribuição
Dutasterida
Os dados farmacocinéticos após doses orais únicas e repetidas mostram que a dutasterida tem um grande volume de distribuição (300 a 500 L). A dutasterida está altamente ligada à albumina plasmática (99,0%) e à glicoproteína ácida alfa-1 (AAG, 96,6%).
Em um estudo com indivíduos saudáveis (n = 26) recebendo dutasterida 0,5 mg / dia por 12 meses, as concentrações de dutasterida de sêmen atingiram uma média de 3,4 ng / mL (variação: 0,4 a 14 ng / mL) em 12 meses e, semelhante ao soro, atingiram concentrações no estado estacionário aos 6 meses. Em média, aos 12 meses, 11,5% das concentrações séricas de dutasterida são divididas em sêmen.
Tamsulosina
O volume aparente médio de distribuição de tamsulosina no estado estacionário após administração intravenosa a 10 adultos do sexo masculino saudáveis foi de 16 L, o que sugere uma distribuição em fluidos extracelulares no corpo.
A tamsulosina está extensivamente ligada às proteínas plasmáticas humanas (94% a 99%), principalmente AAG, com ligação linear em uma ampla faixa de concentração (20 a 600 ng / mL). Os resultados de 2 vias in vitro estudos indicam que a ligação da tamsulosina às proteínas plasmáticas humanas não é afetada pela amitriptilina, diclofenaco, gliburida, sinvastatina mais metabolito do ácido sinvastatina-hidroxi, varfarina, diazepam ou propranolol. Da mesma forma, a tamsulosina não teve efeito na extensão da ligação desses medicamentos.
Metabolismo
Dutasterida
A dutasterida é extensamente metabolizada em humanos. In vitro estudos mostraram que a dutasterida é metabolizada pelas isoenzimas do CYP3A4 e CYP3A5. Ambas as isoenzimas produziram os metabólitos 4'-hidroxidutasterida, 6-hidroxidutasterida e 6,4'-di-hidroxidutasterida. Além disso, o metabolito 15-hidroxidutasterida foi formado pelo CYP3A4. A dutasterida não é metabolizada in vitro pelo citocromo humano P450 isoenzimas CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 e CYP2E1. No soro humano após a administração em estado estacionário, dutasterida inalterada, 3 metabolitos principais (4'-hidroxidutasterida, 1,2-di-hidrodutasterídeo e 6-hidroxidutasterida) e 2 metabólitos menores (6,4'-di-hidroxidutasterida e 15-hidroxidutasterida), conforme avaliado pela resposta espectrométrica de massa, foram detectados. A estereoquímica absoluta das adições de hidroxila nas posições 6 e 15 não é conhecida. In vitro, os metabólitos 4'-hidroxidutasterida e 1,2-di-hidrodutasterídeo são muito menos potentes que o dutasterídeo contra ambas as isoformas da 5α-redutase humana. A atividade da 6β-hidroxidutasterida é comparável à da dutasterida.
Tamsulosina
Não há bioconversão enantiomérica do isômero de tamsulosina [R (-)] para o isômero S (+) em humanos. A tamsulosina é extensamente metabolizada pelas enzimas do citocromo P450 no fígado e menos de 10% da dose é excretada na urina inalterada. No entanto, o perfil farmacocinético dos metabolitos em humanos não foi estabelecido. In vitro estudos indicam que o CYP3A4 e o CYP2D6 estão envolvidos no metabolismo da tamsulosina, bem como em uma participação menor de outras isoenzimas do CYP. A inibição de enzimas hepáticas metabolizadoras de medicamentos pode levar ao aumento da exposição à tamsulosina. Os metabólitos da tamsulosina sofrem extensa conjugação com glucuronido ou sulfato antes da excreção renal.
Incubações com microssomas hepáticos humanos não mostraram evidências de interações metabólicas clinicamente significativas entre tamsulosina e amitriptilina, albuterol, gliburida e finasterida. No entanto, resultados do in vitro os testes da interação da tamsulosina com diclofenaco e varfarina foram ambíguos.
Excreção
Dutasterida
A dutasterida e seus metabólitos foram excretados principalmente nas fezes. Como porcentagem da dose, houve aproximadamente 5% de dutasterida inalterada (aproximadamente 1% a aproximadamente 15%) e 40% como metabólitos relacionados à dutasterida (aproximadamente 2% a aproximadamente 90%). Apenas quantidades vestigiais de dutasterida inalterada foram encontradas na urina (<1%). Portanto, em média, a dose não contabilizada para aproximadamente 55% (variação: 5% a 97%). A meia-vida de eliminação terminal da dutasterida é de aproximadamente 5 semanas em estado estacionário. A concentração média de dutasterida sérica no estado estacionário foi de 40 ng / mL após 0,5 mg / dia por 1 ano. Após a administração diária, as concentrações séricas de dutasterida atingem 65% da concentração no estado estacionário após 1 mês e aproximadamente 90% após 3 meses. Devido à meia-vida longa do dutasterida, as concentrações séricas permanecem detectáveis (superior a 0,1 ng / mL) por até 4 a 6 meses após a descontinuação do tratamento.
Tamsulosina
Na administração da dose radiomarcada de tamsulosina a 4 voluntários saudáveis, 97% da radioatividade administrada foi recuperada, com urina (76%) representando a via primária de excreção em comparação com fezes (21%) ao longo de 168 horas.
Após administração intravenosa ou oral de uma formulação de liberação imediata, a meia-vida de eliminação da tamsulosina no plasma varia de 5 a 7 horas. Devido à farmacocinética controlada pela taxa de absorção com cápsulas de cloridrato de tamsulosina, a meia-vida aparente da tamsulosina é de aproximadamente 9 a 13 horas em voluntários saudáveis e 14 a 15 horas na população-alvo.
A tamsulosina sofre depuração restritiva em humanos, com uma depuração sistêmica relativamente baixa (2,88 L / h).