Usual Adult Dose for Parkinson's Disease

Initial dose: 100 mg orally 3 times a day

• Dose should be increased to 200 mg orally 3 times a day only if the anticipated incremental clinical benefit is justified

Maximum dose: 600 mg/day

Comments:

• Because of the risk of potentially fatal acute fulminant liver failure, this drug should only be used in patients who are experiencing symptom fluctuations and are not responding satisfactorily to, or are not appropriate candidates for, other adjunctive therapies.
• For patients who do not demonstrate observable symptomatic benefit within 3 weeks of starting therapy, therapy should be discontinued.
• In clinical trials, the first dose of the day was always taken with the first dose of the day of levodopa/carbidopa, and subsequent doses were given 6 and 12 hours later.
• In clinical trials, a majority of patients who had levodopa doses greater than 600 mg/day or had moderate or severe dyskinesias prior to starting therapy, required a dose reduction of levodopa; the average dose reduction of levodopa was about 30%.

Use: As an adjunct to levodopa and carbidopa for the treatment of the signs and symptoms of idiopathic Parkinson's disease.

Renal Dose Adjustments

Mild to moderate renal impairment: No dose adjustment recommended
Severe renal impairment (CrCl less than 25 mL/min): Safety has not been established

Liver Dose Adjustments

Therapy should not be initiated:

• In patients with clinical evidence of liver disease, or
• If 2 ALT or AST values are greater than the upper limit of normal

Discontinue therapy if ALT or AST levels exceed 2 times the upper limit of normal or if clinical signs and symptoms suggest the onset of hepatic dysfunction.

Patients who develop hepatocellular injury while on this drug and are withdrawn from this drug for any reason may be at increased risk for liver injury if this drug is restarted; restarting this drug in patients with a history of tolcapone-induced hepatocellular injury is contraindicated.

Dose Adjustments

Use with caution in patients with severe dyskinesia or dystonia

To optimize response to therapy, reductions in levodopa dose may be necessary. In clinical trials, the majority of patients whose levodopa dose was greater than 600 mg/day or who had moderate or severe dyskinesias before beginning treatment, decreased their daily levodopa dose.

Therapy Discontinuation:

• Abrupt withdrawal or dose reduction should be avoided
• Upon discontinuation/dose reduction, closely monitor patient and adjust other dopaminergic treatments as needed.

Precautions

US BOXED WARNINGS: LIVER FAILURE

• Because of the risk of potentially fatal, acute fulminant liver failure, this drug 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.
• Because of the risk of liver injury and because this drug, 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 this drug.
• This drug should not be initiated if the patient exhibits clinical evidence of liver disease or if two SGPT/ALT or SGOT/AST values are greater than the upper limit of normal. Patients with severe dyskinesia or dystonia should be treated with caution.
• PATIENTS WHO DEVELOP EVIDENCE OF HEPATOCELLULAR INJURY WHILE ON TOLCAPONE, AND ARE WITHDRAWN FROM THE DRUG FOR ANY REASON MAY BE AT INCREASED RISK FOR LIVER INJURY IF THIS DRUG, IS REINTRODUCED. ACCORDINGLY, SUCH PATIENTS SHOULD NOT ORDINARILY BE CONSIDERED FOR RETREATMENT.
• 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 general population (however, underreporting may mean there is a significant underestimation of the increased risk). All 3 cases of fatal fulminant hepatic failure were reported within the first 6 months of drug initiation. Analysis of the laboratory monitoring data in over 3,400 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.
• If used, it is strongly advised to monitor patients for evidence of emergent liver injury. Patients should be advised of the need for self-monitoring for both the classic signs of liver disease (e.g., clay colored stools, jaundice) and the nonspecific signs (eg, fatigue, loss of appetite, lethargy).
• Although a program of periodic laboratory monitoring for evidence of hepatocellular injury is recommended, 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, appropriate tests to exclude the presence of liver disease should be performed. 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, thereafter, periodic monitoring is recommended at clinically relevant intervals. If the dose is increased to 200 mg 3 times a day, liver enzyme monitoring should take place before increasing the dose and then every 2 to 4 weeks for the following 6 months. After 6 months, periodic monitoring is recommended at clinically relevant intervals.
• This drug 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).

CONTRAINDICATIONS:

• Hypersensitivity to this drug or product excipients
• Liver disease
• History of tolcapone-induced hepatocellular injury
• History of nontraumatic rhabdomyolysis or hyperpyrexia possibly related to medication

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Hemodialysis: This drug is highly protein bound, therefore no significant removal by hemodialysis is expected.
Peritoneal dialysis: No data available

Other Comments

Administration advice:

• May be taken with or without food
• In clinical trials, the first dose of the day was always taken together with the first dose of the day of levodopa/carbidopa; subsequent doses were taken approximately 6 and 12 hours later
• This drug may be given with both immediate and sustained release levodopa/carbidopa formulations

General:

• Because of the risks of fatal, acute fulminant liver failure, this drug should only be used in patients with Parkinson's disease on levodopa/carbidopa who are experiencing symptom fluctuations not responding satisfactorily to, or are not appropriate candidates for other adjunctive therapies; this drug should be discontinued if substantial clinical benefit is not observed within 3 weeks.
• This drug 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.

Monitoring:

• Hepatic: Obtain liver enzymes (AST and ALT) at baseline, every 2 to 4 weeks for the first 6 months, then as clinically relevant; if the dose is increased to 200 mg three times a day, liver enzyme monitoring should be obtained prior to increase, every 2 to 4 weeks for 6 months, then as clinically relevant; monitor for signs and symptoms of hepatic dysfunction
• Cardiovascular: Monitor for signs and symptoms of orthostatic hypotension
• Nervous System: Monitor for somnolence and drowsiness
• Dermatologic: Monitor for melanomas; consider periodic skin examinations by dermatologists.
• Psychiatric: Question patients about new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges.

Patient advice:

• Patients should understand the risks of hepatic failure and immediately report any symptoms of hepatic dysfunction.
• Patients should be advised that this drug may cause somnolence and episodes of sudden onset of sleep; patients should not drive or operate hazardous machinery if they experience somnolence and/or an episode of sudden onset of sleep.
• Patients should be instructed to report changes in the size, shape, or color of moles on their skin and should have their skin checked on a regular basis for melanomas.
• Patients should be aware that this drug may cause orthostatic blood pressure changes including fainting and dizziness and patients are advised to avoid standing rapidly after sitting or lying down.
• Women should not breastfeed while taking this drug; women should talk with their healthcare provider if they are pregnant or planning to become pregnant.
• Patients and caregivers should be alerted to the possibility that this drug may cause intense urges to spend money, gamble, and other intense urges and the inability to control these urges; these urges should be reported to their health care provider