Entacapone

Medical use

Entacapone is used in addition to levodopa and carbidopa for people with Parkinson's disease to treat the signs and symptoms of end-of-dose "wearing-off." "Wearing-off" is characterized by the re-appearance of both motor and non-motor symptoms of Parkinson’s disease occurring towards the end of a previous levodopa and carbidopa dose. In clinical trials, entacapone has not been shown to slow progression or reverse Parkinson’s disease.

Entacapone is an orally active drug that can be taken with or without food.

Pregnancy and breastfeeding

Pregnancy category C: risk is not ruled out.

Although there have been animal studies that showed that entacapone was excreted into maternal rat milk, there have been no studies with human breast milk. Caution is advised for mothers taking entacapone while breastfeeding or during pregnancy.

Children

Entacapone safety and efficacy have not been assessed in infants or children.

Liver problems

Biliary excretion is the major route of excretion for entacapone. People with liver dysfunction may require additional caution and more frequent liver function monitoring while taking entacapone.

Kidney problems

There are no significant considerations for people with poor kidney function taking entacapone.

Side effects

The following side effects have been reported by people with Parkinson's disease treated with entacapone:

Movement problems

The most common side effect of entacapone is movement problems, which occur in 25% of people taking entacapone. This drug may cause or worsen dyskinesia for people with Parkinson's disease treated together with levodopa and carbidopa. In particular, "peak-dose dyskinesias" may occur when levodopa levels are at its peak concentration in the serum plasma.

Diarrhea

10% of patients taking entacapone have been shown to experience diarrhea. Diarrhea may occur within 4–12 weeks of initial entacapone use but resolves after discontinuation of the drug. Use of entacapone in the presence of diarrhea can also be associated with weight loss, low potassium levels, and dehydration. In clinical studies, severe diarrhea was the most common reason for discontinuation of entacapone.

Urine color

10% of people taking entacapone experience a change in urine color to orange, red, brown, or black. This side effect is due to entacapone metabolism and excretion in the urine and shown to not be harmful.

Sudden sleep onset

People have reported sudden sleep onset while engaging in daily activities without prior warning of drowsiness. In controlled studies, patients on entacapone had a 2% increased risk of somnolence compared to placebo.

Low blood pressure

Episodes of orthostatic hypotension have been shown to be more common at the start of entacapone use due to increased levels of levodopa.

Behavior problems

Post-marketing data shows that entacapone may change or worsen mental status, leading to behaviors such as delusions, agitation, confusion, and delirium.

People taking entacapone may experience increased urges to participate in gambling, sexual activities, money spending, and other stimulating reward behaviors.

Contraindications

There is a high risk for allergic reactions for people who are hypersensitive to entacapone.

Potential limiting conditions to consider before starting entacapone include:

Mechanism of action

Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT). COMT eliminates biologically active catechols present in catecholamines (dopamine, norepinephrine, and epinephrine) and their hydroxylated metabolites. When administered with a decarboxylase inhibitor, COMT acts as the major metabolizing enzyme for levodopa and metabolizes it to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and in the periphery.

For the treatment of Parkinson’s disease, entacapone is given as an adjunct to levodopa and an aromatic amino acid decarboxylase inhibitor, carbidopa. Entacapone inhibits COMT and the metabolism of levodopa, thus increasing plasma levels of levodopa and causing more constant dopaminergic stimulation in order to reduce the signs and symptoms presented in the disease.

Absorption

The Tmax is approximately 1 hour. Absolute oral bioavailability (F) is 35%.

Distribution

The volume of distribution (V_d) after intravenous injection approximately 20 liters. Entacapone has high binding activity to serum albumin that limits its distribution into tissues.

Metabolism and elimination

Entacapone has a half-life of approximately 0.3–0.7 hours. It is primarily metabolized by the liver with 0.2% of the medication unchanged in urine.