Tolcapone Dosage

Usual Adult Dose for Parkinson's Disease

Initial:
100 mg orally three times daily, always taken together with the first dose of the day of levodopa/carbidopa.

Renal Dose Adjustments

CrCl less than 25 mL/min: not recommended

Liver Dose Adjustments

Clearance and volume of distribution of unbound tolcapone was reduced by almost 50% in patients with moderate cirrhotic liver disease (Child-Pugh Class B). This change may increase the average serum concentration of unbound drug by twofold.

Dose Adjustments

The dose may be increased to 200 mg three times daily only if the anticipated incremental benefit is justified. If the patient fails to show substantial clinical benefit within 3 weeks of start of tolcapone, tolcapone should be discontinued.

If the daily of dose of levodopa exceed 600 mg or if patient had moderate or severe dyskinesia, a decrease in dose may be warranted.

Precautions

Because of the risk of potentially fatal, acute fulminant liver failure, tolcapone is only recommended for use in patients with Parkinson's disease on levodopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies. Because of the risk of liver injury and because tolcapone, when it is effective, provides an observable symptomatic benefit, the patient who fail to show substantial clinical benefit within 3 weeks of initiation of tolcapone, should be withdrawn from therapy. Tolcapone 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 dystonia or severe dyskinesia should be treated with caution. Patients who develop signs and symptoms of hepatocellular injury while on tolcapone and are withdrawn from the drug for any reason may be at increased risk for liver injury if tolcapone is reintroduced. These patients should not ordinarily be considered for retreatment. Severe hepatocellular injury, including fulminant liver failure resulting in death, has been reported in postmarketing experience. As of May 2005, 3 cases of fatal fulminant hepatic failure have been reported from approximately 60,000 patients providing about 40,000 patient years of use worldwide. This incidence may be 10 to 100 times higher than the background incidence in the general population. Underreporting of cases may lead to significant underestimation of the increased risk associated with the administration of tolcapone. All 3 cases were reported within the first six months of initiation of therapy. Physicians who elect to use tolcapone in light of the increased risk of liver injury is strongly advised to evaluate patients for evidence of emergent liver injury. Patients should be advised of the need for self-evaluation for both the classical signs of liver disease (e.g., clay colored stools, jaundice) and the nonspecific ones (e.g., fatigue, loss of appetite, lethargy). Although a program of frequent laboratory evaluation for evidence of hepatocellular injury is deemed essential, it is not established that baseline and 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 advised. Before initiating tolcapone therapy, the physician should conduct appropriate tests to exclude the presence of liver disease. In patients determined to be appropriate candidates for tolcapone therapy, 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 six months of therapy. After the first six months, periodic monitoring is advised at intervals deemed clinically relevant. Although more frequent monitoring increases the likelihood of early detection, the precise schedule for monitoring is a matter of clinical judgment. If the dose is increased to 200 mg three times per day, liver enzyme monitoring should take place before increasing the dose and then be conducted every 2 to 4 weeks for the following six months of tolcapone therapy. After six months, periodic monitoring is advised at intervals deemed clinically relevant. Tolcapone 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, jaundice, anorexia, dark urine, pruritus, and right upper quadrant tenderness).

Tolcapone is contraindicated in patients with liver disease and those who were withdrawn from tolcapone therapy because of evidence of tolcapone-induced hepatocellular injury. It is also contraindicated in patients with a history of nontraumatic rhabdomyolysis or hyperpyrexia, and confusion possibly related to the drug.

Dopaminergic therapy in patients with Parkinson's disease has been associated with orthostatic hypotension. Tolcapone enhances levodopa bioavailability and, therefore, may increase the incidence of orthostatic hypotension.

Episodes of syncope have been reported with tolcapone therapy in clinical trials.

Diarrhea has been associated with tolcapone therapy. Typically, it presents 6 to 12 weeks after tolcapone therapy 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 have suggested that diarrhea associated with tolcapone use may sometimes be associated with anorexia. No consistent description of tolcapone-induced diarrhea has been derived from clinical data, and the mechanism of action is currently unknown. It is advised that all cases of persistent diarrhea should be followed up with an appropriate work-up (including occult blood samples).

Hallucinations have been reported with tolcapone therapy in clinical trials. In general, hallucinations present shortly after the initiation of tolcapone therapy (typically within the first 2 weeks). Clinical trial data have suggested 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 hallucinations onset. Hallucinations were frequently accompanied by confusion and to a lesser extent sleep disorder (insomnia) and excessive dreaming.

Tolcapone may potentiate the dopaminergic adverse effects of levodopa and may cause and/or exacerbate preexisting dyskinesia. Although decreasing the dose of levodopa may ameliorate this adverse effect, many patients in controlled trials continued to experience frequent dyskinesias despite a reduction in their dose of levodopa.

No dosage adjustment is required in patients with mild to moderate renal impairment, however, patients with severe renal impairment should be treated with caution.

Hematuria has been reported with tolcapone therapy in clinical trials.

Cases of severe rhabdomyolysis, with one case of multiorgan system failure rapidly progressing to death, have been reported with tolcapone therapy. The complicated nature of these case reports makes it impossible to determine what role, if any, tolcapone therapy played in their pathogenesis. Severe prolonged motor activity including dyskinesia may be the cause for rhabdomyolysis. Some case reports, however, included fever, alteration of consciousness and muscular rigidity. It is possible, therefore, that the rhabdomyolysis may be a result of the symptom complex resembling the neuroleptic malignant syndrome.

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 tolcapone dose. CPK was elevated in 3 of these cases. 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 experience. These cases are of a complicated nature including the concomitant use of several medications affecting brain monoaminergic (i.e., MAO-I, tricyclic and selective serotonin reuptake inhibitors) and anticholinergic systems. It is difficult, therefore, to determine what role, if any, tolcapone played in the pathogenesis. It may, therefore, be prudent to be particularly cautious if several concomitant medications of these types are administered.

While cases of hyperpyrexia and confusion have been reported in association with tolcapone withdrawal, 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 therapy.

These events are known to be associated with the administration of drugs that increase dopaminergic activity, although they are most often associated with the use of direct dopamine agonists. Retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported in some patients treated with ergot derived dopaminergic agents. While these adverse events 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 not known. Three cases of pleural effusion, one with pulmonary fibrosis, have been reported during clinical trials. These patients were also administered concomitant dopamine agonists (pergolide or bromocriptine) and had a prior history of cardiac disease or pulmonary pathology (nonmalignant lung lesion).

Dialysis

Hemodialysis: tolcapone is highly protein bound, therefore no significant removal of the drug is expected.

Other Comments

Tolcapone may be taken with or without food.

See also...