Entacapone

Pregnancy category C: risk is not ruled out.[2]

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.[2]

Entacapone safety and efficacy have not been assessed in infants or children.[2]

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.[2]

There are no significant considerations for people with poor kidney function taking entacapone.[2]

The most common side effect of entacapone is movement problems, which occur in 25% of people taking entacapone.[2] This drug may cause or worsen dyskinesia for people with Parkinson's disease treated together with levodopa and carbidopa.[2] In particular, "peak-dose dyskinesias" may occur when levodopa levels are at its peak concentration in the serum plasma.[7][8]

10% of patients taking entacapone have been shown to experience diarrhea.[2] 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.[2] In clinical studies, severe diarrhea was the most common reason for discontinuation of entacapone.[9]

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.[9]

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.[2]

Episodes of orthostatic hypotension have been shown to be more common at the start of entacapone use due to increased levels of levodopa.[2]

Post-marketing data shows that entacapone may change or worsen mental status, leading to behaviors such as delusions, agitation, confusion, and delirium.[2]

People taking entacapone may experience increased urges to participate in gambling, sexual activities, money spending, and other stimulating reward behaviors.[2]

Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT).[2] 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.[2]

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 in the periphery (but not, or at most marginally, in the brain[11]) 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.[2]

The time to highest blood plasma concentrations is approximately one hour. The substance undergoes extensive first-pass metabolism. Absolute oral bioavailability (F) is 35%.[2][10]

The volume of distribution (V_d) after intravenous injection is approximately 20 liters. 98% of the circulating entacapone is bound to serum albumin, which limits its distribution into tissues.[2][10]

Entacapone is primarily metabolized to its glucuronide in the liver, and 5% are converted into the Z-isomer.[10] It has a half-life of approximately 0.3–0.7 hours, with only 0.2% being excreted unchanged in the urine.[2]