Tolcapone

The drug tolcapone has been designed to help combat Parkinson's disease.

Overview

As a nitrocatechol-type inhibitor, tolcapone has the ability to work on the catechol-O-methyltransferase (COMT) enzyme with efficiency and potency while also being selective and reversible. In many cases, it might be recommended over entacapone, which is an alternative with similar effects, but there are hepatoxicity concerns that limit its widespread use without detailed physician understanding and a signed agreement from the patient noting that they understand these possibilities. It is a tablet that can often be used at the same time as levodopa and carbidopa in order to work against many of the symptoms that are often present in Parkinson's Disease. There has been a black box warning issued by the Food and Drug Administration (FDA) in the United States. This warning was issued in order to help ensure that the proper type of monitoring was given to patients who were subsequently prescribed the drug. However, since then there have been some voluntary removals from the market by both the manufacturing company as well as some countries: Australia, Bulgaria, Iceland, and Lithuania.

Treated Conditions

  • Parkinson's Disease
  • Parkinsonism
  • Tremors
  • Sluggish Movements
  • Muscle Stiffness
  • Impaired Speech

Type of Medicine

  • Tablets (100mg and 200mg)

Side Effects

Hepatoxicity, or liver toxicity, has been the primary concern with this medication, and because of documented instances, it has been less favored over some of the alternatives. Transaminases have increased in some patients, but there is also some consolation because of the fact that previously healthy people without any liver concerns have only a minimal risks if they take the medication while having enzyme levels monitored at the same time. An increase in the dopaminergic activity can lead to some side effects, and these are most likely to manifest in the digestive system. These digestive systems usually appear in the form of nausea, diarrhea, dizziness, sweating, and dry mouth.

The dyskinesia class of movement disorders encompasses some of the possible side effects of tolcapone, and these may manifest in the form of tics or chorea, as well as other involuntary muscle movements or even reduced voluntary muscle movement response. The best way to limit this type of side effect is to reduce the adjunct levodopa level that is usually given at the same time. Orthostatic hypotension that can result in a fast drop in blood pressure (usually related to quickly standing up) has been noted as a side effect in some cases. This can occur more frequently in the elderly, but anyone on Tasmar should note any issues and rise carefully.

The adverse side effect that has most commonly been related to the discontinuation of the drug in a patient has been diarrhea. Though this was usually only mild or moderate in overall severity, there has been around 3 to 4% of the patients who referred to it as severe in scope. The problem generally resolves after a discontinuation of Tasmar occurs, but there were some who had to be hospitalized even after they stopped consuming the drug. Also, the diarrhea may present quickly after the drug has first been given, but there are cases where it took months to manifest in a patient.

Hallucinations and behavior that seemed psychotic-like did appear during some of the trials, and this led to the early withdrawal of those clients from the testing. It is possible that the reduction of the levodopa dose once these delusional perceptions occur can lead to cessation because some patients in the trials did have theirs resolved through such methods. Some of these mental symptoms might range from aggressive behavior and disorientation on one end of the spectrum to paranoia and psychotic behavior on the other, and so this should be carefully reviewed if occurring.

The trials also showed an increase in some compulsive behaviors with some of the subjects. Things like gambling impulses, sexual urges, spending desires, and binge eating wants were some of the manifestations of this type, and physicians should be sure to ask about this when assessing someone who has been put on a tolcapone treatment regimen. Dosage adjustments might be useful in such cases where this appears.

Dopaminergic agents (ergot derived) has led to some cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion or thickening. Discontinuation of the drug has generally led to clarification, but a complete fix does not always occur. The premise is that the ergoline structure is the culprit in such instances, and as such tolcapone should not manifest in this way. But, it is not known whether the nonergot derived dopaminergic activity increasing drugs such as Tasmar will lead to similar complications.

Patients and their doctors that are being treated for Parkinson's should be vigilant about checking for melanomas because of the increased rate that is seen in those with the disease. It is unknown whether this increase is due to some of the drugs that are used for symptom treatment, and so a regular skin exam is always a good measure to take.

Dosage

Adults can take the 100mg tablet form orally three times per day, and this should be coordinated with the adjunct levodopa and carbidopa that accompanies it. When used with children, the needs and dosage should be determined based on the case at hand. Any missed dose should be taken as soon as possible unless it is about time for the subsequent tablet, and in that case, it should not be doubled. It has been derived that the lethal plasma concentration of tolcapone in animals was greater than 100 μg/mL, and 800mg, given three times daily, has been the highest delivered to humans and resulting in 30 μg/mL plasma levels. It is recommended that someone seek hospitalization for an overdose of the drug.

Drug Interactions

Any drug of the class of monoamine oxidase inhibitors (MAOIs) that is not selective in its ability to target either MAO-A or MAO-B individually should not be used while taking tolcapone. Some of the drugs that are non-selective in this regard include phenelzine and tranylcypromine. Also, there are some concerns with other drugs that are metabolized by COMT, and their levels could be increased if taken at the same time. These interactions can occur with primarily carbidopa and benzerazide, and also with methyldopa, adrenaline, isoprenaline, dobutamine, and apomorphine. However, this type of interaction has not been studied conclusively, and so there is only evidence of increases in benzerazide so far. A similar theoretical interaction with drugs that increase catecholamine concentrations (monoamine oxidase (MAO) inhibitors and noradrenaline reuptake inhibitors, for example) has been surmised, but in practice, the effects of an interaction with this class of drugs have been modest.

Warnings

As mentioned above, the primary warning is in relation to the liver toxicity possibilities. The worst occurrence has been in the form of fulminant liver failure that has led to death in some instances. There have been something like 3 cases out of a global set of patients that numbers over 40,000. However, even such a minimal number is still higher than the expected background incidence in such a number of people. If it is prescribed and there is no clinical improvement over the first 3 weeks, then the drug should be discontinued based on these concerns. Those who already have liver disease or similar issues with that organ should not use this medication.

Somnolence has been seen as an effect in some portions of patients, and so there should a limited amount of activity that requires awareness and alertness. A number of the people who have been on Tasmar have noted that they fell asleep suddenly and without any previous warning as to an onset of tiredness and such. Drowsiness and sleepiness should be monitored closely to help prevent any such mishaps. Also, patients who have already gathered a history of a major psychotic disorder should generally be contraindicated because of the chance that this drug, and others for Parkinson's treatment, could worsen psychosis. Likewise, their psychosis medications can interfere with tolcapone rendering it ineffective either way.

Anyone with severe renal impairment should undergo tolcapone treatment carefully, but those with only mild to moderate kidney impairment will usually not require any adjustment of the dosage. Nursing mothers should be administered cautiously if tolcapone is given because of the fact that many drugs excrete into the milk and it is not known whether tolcapone is one of those or what adverse effects might occur in the nursing child.

Storage

The safe storage is in tight containers that generally consist of bottles of 90, and the room temperature should be between 20°C to 25°C (68°F to 77°F).

Summary

Tolcapone has a greater affinity when binding to the catalytic site of catechol-O-methyltransferase (also known as COMT). In this regard, the drug surpasses the three catecholamines that include levodopa. That makes it effective when administered complementary with the levodopa because more will then be able to cross the blood-brain barrier. However, the drug has been taken from many markets because of the side effects and particularly the liver toxicity that has been seen in some people leading to their death. The drug has since been returned to some markets for marketing after assessments by organizations such as the Committee for Medicinal Products for Human Use (CHMP) who have decided that the benefit that might be obtained in patients with Parkinson's is greater than the minimal risk that it might have on some people in regards to the liver toxicity. It should always be prescribed by a trained medical professional who has experience with the advanced treatment of Parkinson's Disease in patients, and there should then be continued monitoring in order to note any adverse effects. Levodopa and benserazide or levodopa and carbidopa are always given adjunctively due to the mechanism of action and tolcapone's ability to expand their effectiveness.

The brand name by Valeant is Tasmar, and the tablet will generally have the imprint of a "V" on one side with a "Tasmar" imprint on the other side along with a marking indicating 100 or 200mg. The generic version could vary quite a bit as far as these imprints are concerned. The half-life of this drug is better than the entacapone alternative, and it also is able to cross the blood-brain barrier more effectively, and this can lead to better action in both the central nervous system and the periphery of the patient. Some of the most common side effects include digestive symptoms such as nausea and diarrhea as well as a harmless urine discoloration. There could also be a dyskinetic symptom increase and some other less common side effects as well. The risk has to be measured against the reward that might be had from responsiveness to the drug.