药品信息:
PROZAC WEEKLY 90 MG CAPSULE
This medicine is a green, oblong capsule imprinted with "Lilly" and "3004 90 mg".
----------------------------------------
【商品名】百优解Prozac
【原名】百忧解
【通用名】盐酸氟西汀
【药理作用】
氟西汀是神经元摄取5－羟色胺的选择性抑制剂，它的抗抑郁活性证实是与抑制神经元摄取5－羟色胺的能力有直接关系。
病人如有肝损伤可影响百优解的消除。
严重肾损伤病人可导致百优解或其所有代谢物的进一步蓄积。
【药代动力学】
口服氟西汀单次剂量后6－8小时血药浓度达峰。饭后服用百优解不影响药物的吸收量。
【适应症】
百优解适用于抑郁症及其伴发之焦虑的治疗。也可用于治疗神经性贪食症和强迫性障碍。
【用法用量】
抑郁症：建议起始剂量为晨服20mg。如果经数周治疗后，临床症状没有改善，可考虑增加剂量，逐渐增加剂量，比如改为1天2次，早、午各服20mg。
神经性贪食症：建议治疗剂量为每天60mg。
强迫性障碍：建议治疗剂量为每天20-60mg。
以上任何状况下治疗剂量均不能超过每天80mg。
老年患者：建议治疗剂量为每天20mg。
肝功能损伤患者－用量和频度均应减少。
肾功能损伤患者－用量和频度均应减少。氟西汀为口服用药。片剂可溶于一杯水中或直接吞服。
【药物过量】
征兆或症状：
主要为恶心和呕吐。可能出现其它中枢神经兴奋的征兆如激动或抽搐。自上市以来，由于单独服用氟西汀过量所致的死亡病例极端罕见。
治疗：建议进行对症治疗和支持治疗。服用活性炭与催吐或洗胃一样有效甚至更有效。因氟西汀导致的惊厥发作如不能自行缓解，可用地西泮进行治疗。
在氟西汀与其它抗抑郁药共同服用过量时，应格外小心。
【不良反应】
与使用氟西汀有关的最常见的不良反应为：焦虑、紧张、失眠、困倦、疲劳、震颤、多汗、厌食、恶心、腹泻、头晕。
不太常见的反应为：头痛、口干、消化不良、呕吐。
其它严重的不良反应偶见报道，例如晕厥、心律失常、非正常肝反应、甲状腺功能减退或亢进、出血时间延长、急性脑部综合征和惊厥。|
【禁忌症】
禁用于对百优解和/或百优解中任何成分过敏的病人。
【警告】
某些患有与氟西汀有关的皮疹的病人，曾经发展为严重的认为与脉管炎有关的全身反应。与此有关的非常偶然的致命事件也有报道。如发生皮疹或其它任何明显的未知病因的过敏症状均应立即停药。
【注意事项】
据报道，部分病人应用氟西汀后可出现躁狂/轻躁狂。
对驾驶的影响：对操作危险机械包括机动车的病人应予以警告，直至他们确认药物对他们不产生有害的影响为止。
【孕妇及哺乳期妇女用药】
使用氟西汀的安全性还未研究。因此，妊娠期妇女除非必要，否则禁用此药。百优解可从母乳中分泌，因此授乳期妇女慎用百优解。
【儿童用药】
由于缺乏百优解应用于儿童的经验资料，故不宜用于儿童。
【老年患者用药】
临床研究未发现与年龄有关的不良现象产生。
【药物相互作用】
百优解偶尔可增加其它抗抑郁药的血药水平。
据报道，糖尿病人在应用百优解治疗期间有可能出现低血糖症，中断治疗后有可能出现高血糖症。应适当调整胰岛素用量和/或口服降血糖药。
百优解与单胺氧化酶抑制剂（MAOI）不能同时服用，也不能在中断MAOI治疗后14日内使用。中断氟西汀治疗和应用MAOI治疗的间隔期限应严格遵守5周的时间。
【贮藏】室温15-25°C保存，
【有效期】3年。
Prozac® (fluoxetine hydrochloride) is a psychotropic drug for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder (Sarafem®, fluoxetine hydrochloride). It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)
oxy]propylamine hydrochloride and has the empirical formula of C17H18F3NO•HCl. Its
molecular weight is 345.79. The structural formula is:
Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. Each Pulvule® contains fluoxetine hydrochloride equivalent to 10 mg (32.3 µmol), 20 mg (64.7 µmol), or 40 mg (129.3 µmol) of fluoxetine. The Pulvules also contain starch, gelatin, silicone, titanium dioxide, iron oxide, and other inactive ingredients. The 10- and 20-mg Pulvules also contain FD&C Blue No. 1, and the 40-mg Pulvule also contains FD&C Blue No. 1 and FD&C Yellow No. 6. Each tablet contains fluoxetine hydrochloride equivalent to 10 mg (32.3 µmol) of fluoxetine. The tablets also contain microcrystalline cellulose, magnesium stearate, crospovidone, hypromellose, titanium dioxide, polyethylene glycol, and yellow iron oxide. In addition to the above ingredients, the 10-mg tablet contains FD&C Blue No. 1 aluminum lake and polysorbate 80. The oral solution contains fluoxetine hydrochloride equivalent to 20 mg/5 mL (64.7 µmol) of fluoxetine. It also contains alcohol 0.23%, benzoic acid, flavoring agent, glycerin, purified water, and sucrose. Prozac Weekly™ capsules, a delayed-release formulation, contain enteric-coated pellets of fluoxetine hydrochloride equivalent to 90 mg (291 µmol) of fluoxetine. The capsules also contain D&C Yellow No. 10, FD&C Blue No. 2, gelatin, hypromellose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, triethyl citrate, and other inactive ingredients.
CLINICAL PHARMACOLOGY
Pharmacodynamics
The antidepressant, antiobsessive-compulsive, and antibulimic actions of fluoxetine are
presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and α1-adrenergic receptors has been hypothesized
to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs.
Absorption, Distribution, Metabolism, and Excretion
Systemic bioavailability - In man, following a single oral 40-mg dose, peak plasma
concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. The Pulvule, tablet, oral solution, and Prozac Weekly capsule dosage forms of fluoxetine are bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, fluoxetine may be administered with or without food. Prozac Weekly capsules, a delayed-release formulation, contain enteric-coated pellets that resist dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. The enteric coating delays the onset of absorption of fluoxetine 1 to 2 hours relative to the immediate-release formulations.
Protein binding - Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully eva luated, but may be important (see PRECAUTIONS).
Enantiomers - Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine
enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state.
Metabolism - Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney.
Clinical issues related to metabolism/elimination - The complexity of the metabolism of fluoxetine has several consequences that may potentially affect fluoxetine's clinical use. Variability in metabolism - A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as " poor metabolizers" of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit. Because fluoxetine's metabolism, like that of a number of other compounds including TCAs and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions (see Drug Interactions under PRECAUTIONS).
Accumulation and slow elimination - The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine's metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks.
The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of Prozac.
Weekly dosing - Administration of Prozac Weekly once weekly results in increased
fluctuation between peak and trough concentrations of fluoxetine and norfluoxetine compared with once-daily dosing [for fluoxetine: 24% (daily) to 164% (weekly) and for norfluoxetine:
17% (daily) to 43% (weekly)]. Plasma concentrations may not necessarily be predictive of clinical response. Peak concentrations from once-weekly doses of Prozac Weekly capsules of fluoxetine are in the range of the average concentration for 20-mg once-daily dosing. Average trough concentrations are 76% lower for fluoxetine and 47% lower for norfluoxetine than the concentrations maintained by 20-mg once-daily dosing. Average steady-state concentrations of either once-daily or once-weekly dosing are in relative proportion to the total dose administered. Average steady-state fluoxetine concentrations are approximately 50% lower following the once-weekly regimen compared with the once-daily regimen. Cmax for fluoxetine following the 90-mg dose was approximately 1.7-fold higher than the Cmax value for the established 20-mg once-daily regimen following transition the next day to the once-weekly regimen. In contrast, when the first 90-mg once-weekly dose and the last 20-mg once-daily dose were separated by 1 week, Cmax values were similar. Also, there was a transient increase in the average steady-state concentrations of fluoxetine observed following transition the next day to the once-weekly regimen. From a pharmacokinetic perspective, it may be better to separate the first 90-mg weekly dose and the last 20-mg once-daily dose by 1 week (see DOSAGE AND ADMINISTRATION).
Liver disease - As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Renal disease - In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients (see Use in patients with concomitant illness under PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Age
Geriatric pharmacokinetics - The disposition of single doses of fluoxetine in healthy elderly subjects (>65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy depressed patients (=60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse events was observed in those elderly patients.
Pediatric pharmacokinetics (children and adolescents) - Fluoxetine pharmacokinetics were eva luated in 21 pediatric patients (10 children ages 6 to <13, 11 adolescents ages 13 to <18) diagnosed with major depressive disorder or obsessive-compulsive disorder (OCD). Fluoxetine 20 mg/day was administered for up to 62 days. The average steady-state concentrations of fluoxetine in these children were 2-fold higher than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine steady-state concentrations in these children were 1.5-fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be almost entirely explained by differences in weight. No gender-associated difference in fluoxetine pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma concentrations were observed in another study in 94 pediatric patients (ages 8 to <18) diagnosed with major depressive disorder.
Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing.
---------------------------------------------------------------
附件:

2010101718590510.pdf