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  药店国别: 法国药房
产地国家: 法国
所属类别: 神经系统药物->帕金森症
处方药:处方药
包装规格: 100毫克/瓶
计价单位:
  点击放大  
生产厂家中文参考译名:
Meda Pharmaceuticals
生产厂家英文名:
Meda Pharmaceuticals
该药品相关信息网址1:
https://www.medicines.org.uk/emc/PIL.15884.latest.pdf
该药品相关信息网址2:
https://www.medicines.org.uk/emc/medicine/15900
原产地英文商品名:
TASMAR CPR 100mg BT100
原产地英文药品名:
TOLCAPONE
中文参考商品译名:
答是美 100毫克/瓶
中文参考药品译名:
托卡朋
原产地国家批准上市年份:
1998/01/29
英文适应病症1:
The treatment of advanced Parkinson's disease
临床试验期:
完成
中文适应病症参考翻译1:
治疗晚期帕金森病
药品信息:

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 详细处方信息以本药内容附件PDF文件(20105622060132.pdf)的“原文Priscribing Information”为

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部分中文TASMAR处方资料(仅供参考)

    托卡朋(Tolcapone)属于可逆性儿茶酚-氧位-甲基转移酶抑制剂(COMT-I),它对中枢及外周均有作用,和复方左旋多巴合用,用于治疗晚期帕金森病。
  
历史信息 
    世界上第一个托卡朋药物是瑞士罗氏制药生产的答是美(Tasmar),该药于1997年8月被批准上市。因Tasmar潜在的肝毒性,1998年11月在欧洲被停用,美国继续出售。随后7年中,欧盟药品管理委员会(EMEA)继续进行托卡朋的临床试验,最终得出结论,在益处与危险的平衡中,托卡朋给患者带来的益处更多。于是,在2004年7月,EMEA发表一项公开声明,宣布解除对Tasmar的停售。至此,托卡朋成为世界上第一个被EMEA禁用后又重新启用的药物。 
  
药理作用 
    COMT-I在外周能阻断左旋多巴转换成3-O-甲基多巴;而后者在多巴脱羧酶抑制剂存在下,是左旋多巴降解的主要途径。托卡朋因此能增加左旋多巴的生物利用度,使更多的左旋多巴经血脑屏障进入中枢,然后转化成多巴胺而改善其“耗竭”现象。 
  
药代动力学 
    口服托卡朋后,吸收迅速,在50-400毫克剂量范围内呈线性,这不依赖于左旋多巴/卡比多巴联合给药。托卡朋绝对生物利用度约65%。托卡朋的清除半衰期是2-3小时,且无明显药物积累。在100毫克或200毫克一日三次的剂量时,Cmax分别约为3微克/毫升和6微克/毫升。托卡朋因其高血浆蛋白结合率而并不广泛分布入组织稳态分布容积很小(9升)。托卡朋在排泄之前几乎完全被代谢,在尿中仅发现很少量(占使用剂量的0.5%)的原形。 
  
药物相互作用 
    α-甲基多巴酚丁胺、阿朴吗啡和异丙肾上腺素等与托卡朋合用时,这些药物应减量。当托卡朋和左旋多巴/卡比多巴与去甲丙咪嗪合用时,患者的血压、脉率与去甲丙咪嗪血浆浓度无明显改变,后者不良反应的发生频率稍有增加。因此,去甲丙咪嗪用于正接受托卡朋和左旋多巴/卡比多巴的帕金森病患者时应谨慎。 
  
临床研究 
    临床试验结果表明,托卡朋能明显降低帕金森病患者的统一帕金森病等级量表(UPDRS)评分,改善该病患者的临床症状和体征,托卡朋组患者在治疗后Hoehn&Yahr分别有所减低,有“开-关”现象患者的“关”期有所缩短。临床试验表明,托卡朋是帕金森病安全有效的辅助治疗药物,尤其能让晚期帕金森病患者的生活质量得到明显的提高。 

不良反应 
    托卡朋常见的不良反应有异动症、失眠、恶心、呕吐、腹泻、体位性低血压及肝损害等。除肝损害外,其余在调整药物剂量后即可消失。服用托卡朋片的患者要进行定期的肝功能监测,尤其在服用该药的前3个月。

TASMAR®
(tolcapone) Tablets

Before prescribing TASMAR, the physician should be thoroughly familiar with the details of  this prescribing information.

TASMAR SHOULD NOT BE USED BY PATIENTS UNTIL THERE HAS BEEN A COMPLETE DISCUSSION OF THE RISKS AND THE PATIENT HAS PROVIDED WRITTEN ACKNOWLEDGEMENT THAT THE RISKS HAVE BEEN EXPLAINED

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DRUG DESCRIPTION
TASMAR® is available as tablets containing 100 mg or 200 mg tolcapone.

Tolcapone, an inhibitor of catechol-O-methyltransferase (COMT), is used in the treatment of Parkinson'sbidopa therapy. It is a yellow,as odorless,an adjunct non- to hygroscopic, crystalline compound with a relative molecular mass of 273.25. The chemical name of tolcapone is 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone. Its empirical formula is C14H11NO5 and its structural formula is:

Inactive ingredients
Core: lactose monohydrate, microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone K-30, sodium starch glycolate, talc and magnesium stearate. Film coating: hydroxypropyl methylcellulose, titanium dioxide, talc, ethylcellulose, triacetin and sodium lauryl sulfate, with the following dye systems: 100 mg — yellow and red iron oxide; 200 mg — red iron oxide.

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INDICATIONS
TASMAR is indicated as an adjunct to levodopa and carbidopa for the treatment of the signs and symptoms of idiopathic Parkinson's acute fulminant liver failure, TASMAR (tolcapone) should ordinarily be used in patients with Parkinson's experiencing symptom disease fluctuations -dopa/carbidopaand are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies. Because of the risk of liver injury and because TASMAR, when it is effective, provides an observable symptomatic benefit, the patient who fails to show substantial clinical benefit within 3 weeks of initiation of treatment, should be withdrawn from TASMAR.

The effectiveness of TASMAR was demonstrated in randomized controlled trials in patients receiving concomitant levodopa therapy with carbidopa or another aromatic amino acid decarboxylase inhibitor who experienced end of dose wearing-off phenomena as well as in patients who did not experience such phenomena (see CLINICAL PHARMACOLOGY: Clinical Studies).

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DOSAGE AND ADMINISTRATION
Because of the risk of potentially fatal, acute fulminant liver failure, TASMAR (tolcapone) should ordinarily be used in patients with Parkinson's disease on l-dopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies (see INDICATIONS and DOSAGE AND ADMINISTRATION sections).

BECAUSE OF THE RISK OF LIVER INJURY AND BECAUSE TASMAR WHEN IT IS EFFECTIVE PROVIDES AN OBSERVABLE SYMPTOMATIC BENEFIT, THE PATIENT WHO FAILS TO SHOW SUBSTANTIAL CLINICAL BENEFIT WITHIN 3 WEEKS OF INITIATION OF TREATMENT, SHOULD BE WITHDRAWN FROM TASMAR.

TASMAR therapy should not be initiated if the patient exhibits clinical evidence of liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal. Patients with severe dyskinesia or dystonia should be treated with caution (see PRECAUTIONS: Rhabdomyolysis).

Patients who develop evidence of hepatocellular injury while on TASMAR and are withdrawn from the drug for any reason may be at increased risk for liver injury if TASMAR is reintroduced. Accordingly, such patients should not ordinarily be considered for retreatment.Treatment with TASMAR should always be initiated at a dose of 100 mg tid, always as an adjunct to levodopa/carbidopa therapy. The recommended daily dose of TASMAR is also 100 mg tid. In clinical trials, elevations in ALT occurred more frequently at the dose of 200 mg tid. While it is unknown whether the risk of acute fulminant liver failure is increased at the 200-mg dose, it would be prudent to use 200 mg only if the anticipated incremental clinical benefit is justified (see BOXED WARNING, WARNINGS, PRECAUTIONS: Laboratory Tests).

If a patient fails to show the expected incremental benefit on the 200-mg dose after a total of 3 weeks of treatment (regardless of dose), TASMAR should be discontinued.In clinical trials, the first dose of the day of TASMAR was always taken together with the first dose of the day of levodopa/carbidopa, and the subsequent doses of TASMAR were given approximately 6 and 12 hours later.

In clinical trials, the majority of patients required a decrease in their daily levodopa dose if their daily dose of levodopa was > 600 mg or if patients had moderate or severe dyskinesias before beginning treatment.

To optimize an individual patient's response, reductions in daily levodopa dose may be necessary. In clinical trials, the average reduction in daily levodopa dose was about 30% in those patients requiring a levodopa dose reduction. (Greater than 70% of patients with levodopa doses above 600 mg daily required such a reduction.)

TASMAR can be combined with both the immediate and sustained release formulations of levodopa/carbidopa.

TASMAR may be taken with or without food (see CLINICAL PHARMACOLOGY).

Patients With Impaired Hepatic Function
TASMAR therapy should not be initiated if any patient with liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal. (See BOXED WARNING, WARNINGS, and CLINICAL PHARMACOLOGY).

Patients With Impaired Renal Function
No dose adjustment of TASMAR is recommended for patients with mild to moderate renal impairment. However, patients with severe renal impairment should be treated with caution. The safety of tolcapone has not been examined in subjects who had creatinine clearance less than 25 mL/min (see CLINICAL PHARMACOLOGY).

Withdrawing Patients From TASMAR
As with any dopaminergic drug, withdrawal or abrupt reduction in the TASMAR dose may lead to emergence of signs and symptoms of Parkinson's disease or Hyperpyrexia and Confusion, a syndrome complex resembling the neuroleptic malignant syndrome (see PRECAUTIONS: Events Reported With Dopaminergic Therapy). If a decision is made to discontinue treatment with TASMAR, then it is recommended to closely monitor the patient and adjust other dopaminergic treatments as needed. This syndrome should be considered in the differential diagnosis for any patient who develops a high fever or severe rigidity. Tapering TASMAR has not been systematically evaluated. As the duration of COMT inhibition with TASMAR is generally 5 to 6 hours on average, decreasing the frequency of dosage to twice or once a day may not in itself prevent withdrawal effects.

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HOW SUPPLIED
TASMAR is supplied as film-coated tablets containing 100 mg or 200 mg tolcapone. The 100 mg beige tablet and the 200 mg reddish-brown tablet are hexagonal and biconvex. Imprinted with black ink on one side of the tablet is TASMAR and the tablet strength (100 or 200), on the other side is a V.
TASMAR 100 mg Tablets: bottles of 90 (NDC 0187-0938-01).
TASMAR 200 mg Tablets: bottles of 90 (NDC 0187-0939-01).

Storage
Store at controlled room temperature 20° to 25°C (68° to 77°F) in tight containers as defined in USP/NF.

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SIDE EFFECTS
Cases of severe hepatocellular injury, including fulminant liver failure resulting in death, have been reported in postmarketing use. As of May 2005, 3 cases of fatal fulminant hepatic failure have been reported from more than 40,000 patient years of worldwide use. This incidence may be 10- to 100-fold higher than the background incidence in the general population. All 3 cases were reported within the first six months of initiation of treatment with TASMAR. Analysis of the laboratory monitoring data in over 3,400 TASMARtreated patients participating in clinical trials indicated that increases in SGPT/ALT or SGOT/AST, when present, generally occurred within the first 6 months of treatment with TASMAR.

The imprecision of the estimated increase is due to uncertainties about the base rate and the actual number of cases occurring in association with TASMAR. The incidence of idiopathic potentially fatal fulminant hepatic failure (ie, not due to viral hepatitis or alcohol) is low. One estimate, based upon transplant registry data, is approximately 3/1,000,000 patients per year in the United States. Whether this estimate is an appropriate basis for estimating the increased risk of liver failure among TASMAR users is uncertain. TASMAR users, for example, differ in age and general health status from candidates for liver transplantation.

Similarly, underreporting of cases may lead to significant underestimation of the increased risk associated with the use of TASMAR.

During the premarketing development of tolcapone, two distinct patient populations were studied, patients with end-of-dose wearing-off phenomena and patients with stable responses to levodopa therapy. All patients received concomitant treatment with levodopa preparations, however, and were similar in other clinical aspects. Adverse events are, therefore, shown for these two populations combined.

The most commonly observed adverse events ( > 5%) in the double-blind, placebo-controlled trials (N=892) associated with the use of TASMAR not seen at an equivalent frequency among the placebotreated patients were dyskinesia, nausea, sleep disorder, dystonia, dreaming excessive, anorexia, cramps muscle, orthostatic complaints, somnolence, diarrhea, confusion, dizziness, headache, hallucination, vomiting, constipation, fatigue, upper respiratory tract infection, falling, sweating increased, urinary tract infection, xerostomia, abdominal pain, urine discoloration.

Approximately 16% of the 592 patients who participated in the double-blind, placebo-controlled trials discontinued treatment due to adverse events compared to 10% of the 298 patients who received placebo. Diarrhea was by far the most frequent cause of discontinuation (approximately 6% in tolcapone patients vs 1% on placebo).

Adverse Event Incidence in Controlled Clinical Studies
Table 4 lists treatment emergent adverse events that occurred in at least 1% of patients treated with tolcapone participating in the double-blind, placebo-controlled studies and were numerically more common in at least one of the tolcapone groups. In these studies, either tolcapone or placebo were added to levodopa/carbidopa (or benserazide).

The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse events incidence rate in the population studied.

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DRUG INTERACTIONS
Protein Binding
Although tolcapone is highly protein bound, in vitro studies have shown that tolcapone at a concentration of 50 μg/mL did not displace other highly protein-bound drugs from their binding sites at therapeutic concentrations. The experiments included warfarin (0.5 to 7.2 μg/mL), phenytoin (4.0 to 38.7 μg/mL), tolbutamide (24.5 to 96.1 μg/mL) and digitoxin (9.0 to 27.0 μg/mL).

Drugs Metabolized by Catechol-O-Methyltransferase (COMT)
Tolcapone may influence the pharmacokinetics of drugs metabolized by COMT. However, no effects were seen on the pharmacokinetics of the COMT substrate carbidopa. The effect of tolcapone on the pharmacokinetics of other drugs of this class such as α-methyldopa, dobutamine, apomorphine, and isoproterenol has not been evaluated. A dose reduction of such compounds should be considered when they are coadministered with tolcapone.

Effect of Tolcapone on the Metabolism of Other Drugs
In vitro experiments have been performed to assess the potential of tolcapone to interact with isoenzymes of cytochrome P450 (CYP). No relevant interactions with substrates for CYP 2A6 (coumadin), CYP 1A2 (caffeine), CYP 3A4 (midazolam, terfenadine, cyclosporine), CYP 2C19 (S-mephenytoin) and CYP 2D6 (desipramine) were observed in vitro. The absence of an interaction with desipramine, a drug metabolized by cytochrome P450 2D6, was also confirmed in an in vivo study where tolcapone did not change the pharmacokinetics of desipramine.

Due to its affinity to cytochrome P450 2C9 in vitro, tolcapone may interfere with drugs, whose clearance is dependent on this metabolic pathway, such as tolbutamide and warfarin.

However, in an in vivo interaction study, tolcapone did not change the pharmacokinetics of tolbutamide. Therefore, clinically relevant interactions involving cytochrome P450 2C9 appear unlikely. Similarly, tolcapone did not affect the pharmacokinetics of desipramine, a drug metabolized by cytochrome P450 2D6, indicating that interactions with drugs metabolized by that enzyme are unlikely. Since clinical information is limited regarding the combination of warfarin and tolcapone, coagulation parameters should be monitored when these two drugs are coadministered.

Drugs That Increase Catecholamines
Tolcapone did not influence the effect of ephedrine, an indirect sympathomimetic, on hemodynamic parameters or plasma catecholamine levels, either at rest or during exercise.

Since tolcapone did not alter the tolerability of ephedrine, these drugs can be coadministered.

When TASMAR was given together with levodopa/carbidopa and desipramine, there was no significant change in blood pressure, pulse rate and plasma concentrations of desipramine.

Overall, the frequency of adverse events increased slightly. These adverse events were predictable based on the known adverse reactions to each of the three drugs individually.

Therefore, caution should be exercised when desipramine is administered to Parkinson's disease patients being treated with TASMAR and levodopa/carbidopa.

In clinical trials, patients receiving TASMAR/levodopa preparations reported a similar adverse event profile independent of whether or not they were also concomitantly administered selegiline (a selective MAO-B inhibitor).

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WARNINGS
(SEE BOXED WARNING) Because of the risk of potentially fatal, acute fulminant liver failure, TASMAR (tolcapone) should ordinarily be used in patients with Parkinson's experiencing symptom fluctuations and are notdisease -dopa/carbidopa responding satisfactorily to or are not appropriate candidates for other adjunctive therapies (see INDICATIONS and DOSAGE AND ADMINISTRATION sections).

Because of the risk of liver injury and because TASMAR, when it is effective, provides an observable symptomatic benefit, the patient who fails to show substantial clinical benefit within 3 weeks of initiation of treatment, should be withdrawn from TASMAR.

TASMAR therapy should not be initiated if the patient exhibits clinical evidence of liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal. Patients with severe dyskinesia or dystonia should be treated with caution (see PRECAUTIONS: Rhabdomyolysis).

Patients who develop evidence of hepatocellular injury while on TASMAR and are withdrawn from the drug for any reason may be at increased risk for liver injury if TASMAR is reintroduced. Accordingly, such patients should not ordinarily be considered for retreatment. In controlled Phase 3 trials, increases to more than 3 times the upper limit of normal in ALT or AST occurred in approximately 1% of patients at 100 mg tid and 3% of patients at 200 mg tid. Females were more likely than males to have an increase in liver enzymes (approximately 5% vs 2%). Approximately one third of patients with elevated enzymes had diarrhea. Increases to more than 8 times the upper limit of normal in liver enzymes occurred in 0.3% at 100 mg tid and 0.7% at 200 mg tid. Elevated enzymes led to discontinuation in 0.3% and 1.7% of patients treated with 100 mg tid and 200 mg tid, respectively. Elevations usually occurred within 6 weeks to 6 months of starting treatment. In about half the cases with elevated liver enzymes, enzyme levels returned to baseline values within 1 to 3 months while patients continued TASMAR treatment. When treatment was discontinued, enzymes generally declined within 2 to 3 weeks but in some cases took as long as 1 to 2 months to return to normal.

Monoamine oxidase (MAO) and COMT are the two major enzyme systems involved in the metabolism of catecholamines. It is theoretically possible, therefore, that the combination of TASMAR and a non-selective MAO inhibitor (eg, phenelzine and tranylcypromine) would result in inhibition of the majority of the pathways responsible for normal catecholamine metabolism.

For this reason, patients should ordinarily not be treated concomitantly with TASMAR and a non-selective MAO inhibitor.

Tolcapone can be taken concomitantly with a selective MAO-B inhibitor (eg, selegiline).

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PRECAUTIONS
Hypotension/Syncope
Dopaminergic therapy in Parkinson's disease patients has been associated with orthostatic hypotension. Tolcapone enhances levodopa bioavailability and, therefore, may increase the occurrence of orthostatic hypotension. In TASMAR clinical trils,orthostatic hypotension was documented at least once in 8%, 14% and 13% of the patients treated with placebo, 100 mg and 200 mg TASMAR tid, respectively. A total of 2%, 5% and 4% of the patients treated with placebo, 100 mg and 200 mg TASMAR tid, respectively, reported orthostatic symptoms at some time during their treatment and also had at least one episode of orthostatic hypotension documented (however, the episode of orthostatic symptoms itself was invariably not accompanied by vital sign measurements). Patients with orthostasis at baseline were more likely than patients without symptoms to have orthostatic hypotension during the study, irrespective of treatment group. In addition, the effect was greater in tolcapone-treated patients than in placebo-treated patients. Baseline treatment with dopamine agonists or selegiline did not appear to increase the likelihood of experiencing orthostatic hypotension when treated with TASMAR. Approximately 0.7% of the patients treated with TASMAR (5% of patients who were documented to have had at least one episode of orthostatic hypotension) eventually withdrew from treatment due to adverse events presumably related to hypotension.

In controlled Phase 3 trials, approximately 5%, 4% and 3% of tolcapone 200 mg tid, 100 mg tid and placebo patients, respectively, reported at least one episode of syncope. Reports of syncope were generally more frequent in patients in all three treatment groups who had an episode of documented hypotension (although the episodes of syncope, obtained by history, were themselves not documented with vital sign measurement) compared to patients who did not have any episodes of documented hypotension.

Diarrhea
In clinical trials, diarrhea developed in approximately 8%, 16% and 18% of patients treated with placebo, 100 mg and 200 mg TASMAR tid, respectively. While diarrhea was generally regarded as mild to moderate in severity, approximately 3% to 4% of patients on tolcapone had diarrhea which was regarded as severe. Diarrhea was the adverse event which most commonly led to discontinuation, with approximately 1%, 5% and 6% of patients treated with placebo, 100 mg and 200 mg TASMAR tid, respectively, withdrawing from the trials prematurely. Discontinuing

TASMAR for diarrhea was related to the severity of the symptom. Diarrhea resulted in withdrawal in approximately 8%, 40% and 70% of patients with mild, moderate and severe diarrhea, respectively. Although diarrhea generally resolved after discontinuation of TASMAR, it led to hospitalization in 0.3%, 0.7% and 1.7% of patients in the placebo, 100 mg and 200 mg TASMAR tid groups.

Typically, diarrhea presents 6 to 12 weeks after tolcapone is started, but it may appear as early as 2 weeks and as late as many months after the initiation of treatment. Clinical trial data suggested that diarrhea associated with tolcapone use may sometimes be associated with anorexia (decreased appetite).

No consistent description of tolcapone-induced diarrhea has been derived from clinical trial data, and the mechanism of action is currently unknown.

It is recommended that all cases of persistent diarrhea should be followed up with an appropriate workup (including occult blood samples).

Hallucinations
In clinical trials, hallucinations developed in approximately 5%, 8% and 10% of patients treated with placebo, 100 mg and 200 mg TASMAR tid, respectively. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 0.3%, 1.4% and 1.0% of patients treated with placebo, 100 mg and 200 mg TASMAR tid, respectively. Hallucinations led to hospitalization in 0.0%, 1.7% and 0.0% of patients in the placebo, 100 mg and 200 mg

TASMAR tid groups, respectively.

In general, hallucinations present shortly after the initiation of therapy with tolcapone (typically within the first 2 weeks). Clinical trial data suggest that hallucinations associated with tolcapone use may be responsive to levodopa dose reduction. Patients whose hallucinations resolved had a mean levodopa dose reduction of 175 mg to 200 mg (20% to 25%) after the onset of the hallucinations. Hallucinations were commonly accompanied by confusion and to a lesser extent sleep disorder (insomnia) and excessive dreaming.

Dyskinesia
TASMAR may potentiate the dopaminergic side effects of levodopa and may cause and/or exacerbate preexisting dyskinesia. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled trials continued to experience frequent dyskinesias despite a reduction in their dose of levodopa. The rates of withdrawal for dyskinesia were 0.0%, 0.3% and 1.0% for placebo, 100 mg and 200 mg TASMAR tid, respectively.

Rhabdomyolysis
Cases of severe rhabdomyolysis, with one case of multiorgan system failure rapidly progressing to death, have been reported. The complicated nature of these cases makes it impossible to determine what role, if any, TASMAR played in their pathogenesis. Severe prolonged motor activity including dyskinesia may account for rhabdomyolysis. Some cases, however, included fever, alteration of consciousness and muscular rigidity. It is possible, therefore, that the rhabdomyolysis may be a result of the syndrome described in Hyperpyrexia and Confusion (see PRECAUTIONS: Events Reported With Dopaminergic Therapy).

Renal Impairment
No dosage adjustment is needed in patients with mild to moderate renal impairment, however, patients with severe renal impairment should be treated with caution (see CLINICAL PHARMACOLOGY: Pharmacokinetics of Tolcapone and DOSAGE AND ADMINISTRATION).

Renal Toxicity
When rats were dosed daily for 1 or 2 years (exposures 6 times the human exposure or greater) there was a high incidence of proximal tubule cell damage consisting of degeneration, single cell necrosis, hyperplasia, karyocytomegaly and atypical nuclei. These effects were not associated with changes in clinical chemistry parameters, and there is no established method for monitoring for the possible occurrence of these lesions in humans. Although it has been speculated that these toxicities may occur as the result of a species-specific mechanism, experiments which would confirm that theory have not been conducted.

Hepatic Impairment
Because of the risk of liver injury, TASMAR therapy should not be initiated in any patient with liver disease. For similar reasons, treatment should not be initiated in patients who have two SGPT/ALT or SGOT/AST values greater than the upper limit of normal (see BOXED WARNING) or any other evidence of hepatocellular dysfunction.

Hematuria
The rates of hematuria in placebo-controlled trials were approximately 2%, 4% and 5% in placebo, 100 mg and 200 mg TASMAR tid, respectively. The etiology of the increase with TASMAR has not always been explained (for example, by urinary tract infection or coumadin therapy). In placebo-controlled trials in the United States (N=593) rates of microscopically confirmed hematuria were approximately 3%, 2% and 2% in placebo, 100 mg and 200 mg TASMAR tid, respectively.

Events Reported With Dopaminergic Therapy
The events listed below are known to be associated with the use of drugs that increase dopaminergic activity, although they are most often associated with the use of direct dopamine agonists. While cases of Hyperpyrexia and Confusion have been reported in association with tolcapone withdrawal (see paragraph below), the expected incidence of fibrotic complications is so low that even if tolcapone caused these complications at rates similar to those attributable to other dopaminergic therapies, it is unlikely that even a single example would have been detected in a cohort of the size exposed to tolcapone.

Hyperpyrexia and Confusion
In clinical trials, four cases of a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, and altered consciousness), similar to that reported in association with the rapid dose reduction or withdrawal of other dopaminergic drugs, have been reported in association with the abrupt withdrawal or lowering of the dose of tolcapone. In 3 of these cases, CPK was elevated as well. One patient died, and the other 3 patients recovered over periods of approximately 2, 4 and 6 weeks. Rare cases of this symptom complex have been reported during marketed use. These cases are of a complicated nature including the concomitant administration of several medications affecting brain monoaminergic (ie, MAO-I, tricyclic and selective serotonin reuptake inhibitors) and anticholinergic systems. It is difficult, therefore, to determine what role, if any, TASMAR played in the pathogenesis. It may, therefore, be prudent to be particularly cautious if several concomitant medications of these types are used.

Fibrotic Complications
Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported in some patients treated with ergot derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.

Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived drugs (eg, tolcapone) that increase dopaminergic activity can cause them is unknown.

Three cases of pleural effusion, one with pulmonary fibrosis, occurred during clinical trials. These patients were also on concomitant dopamine agonists (pergolide or bromocriptine) and had a prior history of cardiac disease or pulmonary pathology (nonmalignant lung lesion).

Melanoma
Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Stalevo for any indication. Ideally, periodic skin examination should be performed by appropriately qualified individuals (e.g., dermatologists).

Laboratory Tests
Although a program of frequent laboratory monitoring for evidence of hepatocellular injury is deemed essential, it is not clear that periodic monitoring of liver enzymes will prevent the occurrence of fulminant liver failure. However, it is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug enhances the likelihood for recovery. Accordingly, the following liver monitoring program is recommended.

Before starting treatment with TASMAR, the physician should conduct appropriate tests to exclude the presence of liver disease. In patients determined to be appropriate candidates for treatment with TASMAR, serum glutamic-pyruvic transaminase (SGPT/ALT) and serum glutamic-oxaloacetic transaminase (SGOT/AST) levels should be determined at baseline and periodically (i.e. every 2 to 4 weeks) for the first 6 months of therapy. After the first six months, periodic monitoring is recommended at intervals deemed clinically relevant. Although more frequent monitoring increases the chances of early detection, the precise schedule for monitoring is a matter of clinical judgement.

If the dose is increased to 200 mg tid (see DOSAGE AND ADMINISTRATION section), liver enzyme monitoring should take place before increasing the dose and then be conducted every 2 to 4 weeks for the following 6 months of therapy. After six months, periodic monitoring is recommended at intervals deemed clinically relevant.

TASMAR should be discontinued if SGPT/ALT or SGOT/AST levels exceed 2 times the upper limit of normal or if clinical signs and symptoms suggest the onset of hepatic dysfunction (persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine, pruritus, and right upper quadrant tenderness).

Special Populations
TASMAR therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal.

Patients with severe dyskinesia or dystonia should be treated with caution (see PRECAUTIONS: Rhabdomyolysis). Patients with severe renal impairment should be treated with caution (see INDICATIONS, DOSAGE AND ADMINISTRATION, BOXED WARNING and WARNINGS).

Carcinogenesis, Mutagenesis and Impairment of Fertility
Carcinogenesis
Carcinogenicity studies in which tolcapone was administered in the diet were conducted in mice and rats. Mice were treated for 80 (female) or 95 (male) weeks with doses of 100, 300 and 800 mg/kg/day, equivalent to 0.8, 1.6 and 4 times human exposure (AUC = 80 ug·hr/mL) at the recommended daily clinical dose of 600 mg. Rats were treated for 104 weeks with doses of 50, 250 and 450 mg/kg/day.

Tolcapone exposures were 1, 6.3 and 13 times the human exposure in male rats and 1.7, 11.8 and 26.4 times the human exposure in female rats. There was an increased incidence of uterine adenocarcinomas in female rats at exposure equivalent to 26.4 times the human exposure. There was evidence of renal tubular injury and renal tubular tumor formation in rats. A low incidence of renal tubular cell adenomas occurred in middle-and high-dose female rats; tubular cell carcinomas occurred in middle- and high-dose male and highdose female rats, with a statistically significant increase in high-dose males. Exposures were equivalent to 6.3 (males) or 11.8 (females) times the human exposure or greater; no renal tumors were observed at exposures of 1 (males) or 1.7 (females) times the human exposure. Minimal-to-marked damage to the renal tubules, consisting of proximal tubule cell degeneration, single cell necrosis, hyperplasia and karyocytomegaly, occurred at the doses associated with renal tumors. Renal tubule damage, characterized by proximal tubule cell degeneration and the presence of atypical nuclei, as well as one adenocarcinoma in a high-dose male, were observed in a 1-year study in rats receiving doses of tolcapone of 150 and 450 mg/kg/day. These histopathological changes suggest the possibility that renal tumor formation might be secondary to chronic cell damage and sustained repair, but this relationship has not been established, and the relevance of these findings to humans is not known. There was no evidence of carcinogenic effects in the long-term mouse study. The carcinogenic potential of tolcapone in combination with levodopa/carbidopa has not been examined.

Mutagenesis
Tolcapone was clastogenic in the in vitro mouse lymphoma/thymidine kinase assay in the presence of metabolic activation. Tolcapone was not mutagenic in the Ames test, the in vitro V79/HPRT gene mutation assay, or the unscheduled DNA synthesis assay. It was not clastogenic in an in vitro chromosomal aberration assay in cultured human lymphocytes, or in an in vivo micronucleus assay in mice.

Impairment of Fertility
Tolcapone did not affect fertility and general reproductive performance in rats at doses up to 300 mg/kg/day (5.7 times the human dose on a mg/m2 basis).

Pregnancy
Pregnancy Category C
Tolcapone, when administered alone during organogenesis, was not teratogenic at doses of up to 300 mg/kg/day in rats or up to 400 mg/kg/day in rabbits (5.7 times and 15 times the recommended daily clinical dose of 600 mg, on a mg/m2 basis, respectively). In rabbits, however, an increased rate of abortion occurred at a dose of 100 mg/kg/day (3.7 times the daily clinical dose on a mg/m2 basis) or greater. Evidence of maternal toxicity (decreased weight gain, death) was observed at 300 mg/kg in rats and 400 mg/kg in rabbits. When tolcapone was administered to female rats during the last part of gestation and throughout lactation, decreased litter size and impaired growth and learning performance in female pups were observed at a dose of 250/150 mg/kg/day (dose reduced from 250 to 150 mg/kg/day during late gestation due to high rate of maternal mortality; equivalent to 4.8/2.9 times the clinical dose on a mg/m2 basis).

Tolcapone is always given concomitantly with levodopa/carbidopa, which is known to cause visceral and skeletal malformations in rabbits. The combination of tolcapone (100 mg/kg/day) with levodopa/carbidopa (80/20 mg/kg/day) produced an increased incidence of fetal malformations (primarily external and skeletal digit defects) compared to levodopa/carbidopa alone when pregnant rabbits were treated throughout organogenesis. Plasma exposures to tolcapone (based on AUC) were 0.5 times the expected human exposure, and plasma exposures to levodopa were 6 times higher than those in humans under therapeutic conditions. In a combination embryo-fetal development study in rats, fetal body weights were reduced by the combination of tolcapone (10, 30 and 50 mg/kg/day) and levodopa/carbidopa (120/30 mg/kg/day) and by levodopa/carbidopa alone. Tolcapone exposures were 0.5 times expected human exposure or greater: levodopa exposures were 21 times the expected human exposure or greater. The high dose of 50 mg/kg/day of tolcapone given alone was not associated with reduced fetal body weight (plasma exposures of 1.4 times the expected human exposure).

There is no experience from clinical studies regarding the use of TASMAR in pregnant women.

Therefore, TASMAR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Women
In animal studies, tolcapone was excreted into maternal rat milk.It is not known whether tolcapone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tolcapone is administered to a nursing woman.

Pediatric Use
There is no identified potential use of tolcapone in pediatric patients.

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OVERDOSE
The highest dose of tolcapone administered to humans was 800 mg tid, with and without levodopa/carbidopa coadministration. This was in a 1-week study in elderly, healthy volunteers. The peak plasma concentrations of tolcapone at this dose were on average 30 μg/mL (compared to 3 μg/mL and 6 μg/mL with 100 mg and 200 mg tolcapone, respectively).

Nausea, vomiting and dizziness were observed, particularly in combination with levodopa/carbidopa.

THE THRESHOLD FOR THE LETHAL PLASMA CONCENTRATION FOR TOLCAPONE BASED ON ANIMAL DATA IS > 100 μG/ML. RESPIRATORY DIFFICULTIES WERE OBSERVED IN RATS AT HIGH ORAL (GAVAGE) AND INTRAVENOUS

DOSES AND IN DOGS WITH RAPIDLY INJECTED INTRAVENOUS DOSES.

Management of Overdose
Hospitalization is advised. General supportive care is indicated. Based on the physicochemical properties of the compound, hemodialysis is unlikely to be of benefit.

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CONTRAINDICATIONS
TASMAR tablets are contraindicated in patients with liver disease, in patients who were withdrawn from TASMAR because of evidence of TASMAR-induced hepatocellular injury or who have demonstrated hypersensitivity to the drug or its ingredients.

TASMAR is also contraindicated in patients with a history of non-traumatic rhabdomyolysis or hyperpyrexia and confusion possibly related to medication

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于2010年5月7日更新

更新日期: 2017-09-11
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