Tolcapone

Mechanism of Action

Tolcapone is a catechol-O-methyltransferase (COMT) inhibitor. Levodopa, a common medication used for Parkinson disease, is normally metabolized by decarboxylase in the periphery to dopamine. Therefore, levodopa is typically administered with a decarboxylase inhibitor like carbidopa to increase the amount of levodopa that reaches the brain and to decrease adverse effects caused by dopamine when produced in the periphery. However, when decarboxylase becomes inhibited by carbidopa, levodopa is metabolized by COMT in the periphery. Therefore, by inhibiting COMT, tolcapone further decreases the degradation of levodopa in the periphery, which allows more levodopa to reach the brain and potentially allows for a decrease in the dosage of levodopa.[1][5]

Administration

Tolcapone is only available as an oral formulation in 100 mg and 200 mg tablets. The recommended starting dose for tolcapone is 100 mg three times a day while concurrently taking levodopa and carbidopa. An increase in dosage to 200 mg three times daily may be warranted if the clinical benefit outweighs the potential risk of increasing therapy.[6] Pharmacokinetic studies have shown the oral bioavailability of tolcapone to be around 60% and an elimination half-life of just under 2 hours.[7]

Adverse Effects

The most common dopaminergic adverse effects while taking tolcapone include nausea, postural hypotension, and dyskinesia. However, one study found a reduction of these adverse effects with a decrease in levodopa dosage. Other common adverse effects include diarrhea, urine discoloration, and drowsiness. Patients may also experience other central nervous system adverse effects such as insomnia, hallucinations, dizziness, headaches, depression, and fatigue.[8]

A rare but serious adverse effect of tolcapone is hepatic dysfunction. Patients with liver toxicity may experience nausea, fatigue, anorexia, dark urine, or right upper quadrant pain. Studies have shown that tolcapone can increase liver enzyme levels, especially AST and ALT, 2 to 3 times the upper limit of normal. In the same study, less than 2% of patients saw an increase greater than three times the upper limit of normal.

Most increases in liver enzymes were transient, even with the continuation of therapy.[3] However, because of the risk of acute liver failure, tolcapone carries a black box warning for liver toxicity. Patients should not be started on tolcapone if they have clinical evidence of liver disease. If a patient’s AST or ALT levels are greater than two times the upper limit of normal, then tolcapone should not be used. Additionally, if a patient experiences liver toxicity while taking tolcapone, they should not have retreatment with tolcapone.[9]

Contraindications

The use of tolcapone is contraindicated in patients who have a history of liver disease. Clinicians should also not initiate tolcapone therapy in patients with an ALT or AST value two times the upper limit of normal. If a patient has a history of neuroleptic malignant syndrome or nontraumatic rhabdomyolysis, tolcapone is contraindicated. Tolcapone should also be avoided in patients who have a hypersensitivity to tolcapone.[10]

Monitoring

The primary monitoring requirement for patients on tolcapone is AST and ALT levels. AST and ALT levels should be checked at baseline, every two to four weeks for the first six months, and then as clinically necessary after that. Prescribers should discontinue tolcapone if AST or ALT levels are greater than two times the upper limit of normal or if a patient presents with signs and symptoms of liver failure.[11] Other monitoring parameters include blood pressure to check for hypotension, a patient's mental status to check for central nervous system adverse effects, and skin examinations since patients with Parkinson disease are at an increased risk for melanoma. Lastly, the healthcare team should monitor patients for signs and symptoms of Parkinson disease. If there is no benefit within three weeks of initiating tolcapone, the prescribing clinician should discontinue therapy.[1]

Toxicity

There is currently no antidote or treatment for overdose of tolcapone. If a patient experiences liver toxicity while on tolcapone, therapy should be discontinued. The mechanism of liver toxicity appears to occur in the metabolism pathway of tolcapone. A toxic intermediate may form, causing damage to the liver.[12]

Enhancing Healthcare Team Outcomes

Most patients with Parkinson disease will be identified in the community by their primary care physician, but ongoing care should involve the efforts of an entire interprofessional healthcare team. Once identified, patients should receive a referral to a neurologic specialist for further workup and diagnosis. Primary care clinicians and neurologists need to maintain communication to improve care coordination and patient-centered care. Pharmacists are also a vital resource for medication management and ensuring patient safety with medications. Medication regimens can become complex in Parkinson disease, so it is important to avoid drug-drug interactions and adverse events, which can be alleviated with the help of a pharmacist. Nursing staff can also provide patient counseling, coordinate with other providers, and act as a primary point of contact for patients and other team members.

Occupational therapists may also be beneficial in patient care depending on symptoms patients experience and their ability to perform everyday activities. Since Parkinson disease is progressive, other specialists who may need to consult in the care of the patient include gastroenterologists, urologists, ophthalmologists, and psychiatrists. The patient should also be actively involved with their care to ensure an interprofessional patient-centered care model.[13] [Level 5]