entacapone/levodopa/carbidopa (Rx)

>10%

Entacapone

• Dyskinesia (25%)
• Nausea (14%)
• Diarrhea (10%)
• Hyperkinesia (10%)
• Urine discoloration (10%)

1-10%

Entacapone

• Hypokinesia (9%), dizziness (8%), Fatigue (6%), hallucinations (1-4%), anxiety (2%), somnolence (2%), asthenia (2%), agitation (1%)
• Increased sweating (2%)
• Purpura (2%)
• Abdominal pain (8%), constipation (6%), vomiting (4%), dry mouth (3%), dyspepsia (2%), flatulence (2%), taste perversion (1%), gastritis (1%)
• Back pain (4%)
• Dyspnea (3%)
• Bacterial infection (1%)

Frequency Not Defined

Levodopa/Carbodopa

• Edema
• Agitation, anxiety, ataxia, bruxism, confusion, daytime somnolence decreased attention span, dyskinesia, dystonia, euphoria, insomnia, fainting, fatigue, increased trembling of hands, insouciance, malaise, memory loss, nightmares, nervousness, restlessness, trismus, vivid dreams
• Alopecia, hot flushes, increased &/or dark perspiration, skin eruptions
• Abdominal pain & discomfort, burning feeling in tongue, constipation, diarrhea, dysgeusia, dry mouth, dysphagia, hiccups, meteorism, sialorrhea, nausea, weight loss
• Muscular spasms, muscular cramp
• Hematuria, dark urine, incontinence, priapism, urine retention
• Blurred vision, diplopia, dilated pupil, oculogyric problems

Entacapone

• Postural hypotension
• Insomnia
• Confusion

Contradindications

Hypersensitivity

Concurrency with nonselective MAOIs (discontinue 2 weeks before starting treatment)

Narrow angle glaucoma

Undiagnosed skin lesions, history of melanoma

Cautions

Hepatic disease, severe cardiovascular/pulmonary disease, bronchial asthma, renal/endocrine disease, open-angle glaucoma

Age >75 yr

History/active psychoses, history of MI or peptic ulcer

Residual atrial, nodal, ventricular arrhythmias

Risk of uncontrollable sexual, gambling or other urges

May be linked to higher melanoma risk in patient with Parkinson disease

May cause NMS if reduced abruptly or discontinued

Risk of syncope

Risk of developing prostate cancer

Diarrhea may occur and be associated entacapone; may cause weight loss, dehydration, and hypokalemia; if severe, may be a sign of drug-induced microscopic colitis

Pregnancy

There are no adequate data on developmental risk associated with use of drug in pregnant women

Animal data

• In animals, administration of carbidopa-levodopa or entacapone during pregnancy was associated with developmental toxicity, including increased incidences of fetal malformations; estimated background risk of major birth defects and miscarriage in indicated population is unknown

Lactation

Levodopa has been detected in human milk after administration of carbidopa-levodopa; there are no data on presence of entacapone or carbidopa in human milk, effects of levodopa, carbidopa, or entacapone on breastfed infant, or on milk production; however, inhibition of lactation may occur because levodopa decreases secretion of prolactin; carbidopa and entacapone are excreted in rat milk; in lactating rat, oral administration of radiolabeled entacapone resulted in levels of entacapone and/or metabolites in milk up to 2 to 3 times that in plasma;

Consider developmental and health benefits of breastfeeding along with mother’s clinical need for drug and any potential adverse effects on breastfed infant or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Levodopa: Crosses blood-brain barrier & converts to dopamine

Carbidopa: Inhibits decarboxylation or breakdown of peripheral levodopa

Entacapone: Selective & reversible inhibitor of COMT

Pharmacokinetics

Absorption

• levodopa: rapid
• carbidopa: slightly slower than levodopa/entacapone
• entacapone: rapid

Peak plasma time

• levodopa: 0.6-2.4 hr
• carbidopa: 2.5-3.4 hr
• entacapone: 1-1.2 hr

Half Life

• levodopa: 1.7 hr
• carbidopa: 1.6-2 hr
• entacapone: 0.8-1 hr

Protein Bound

• levodopa: 10-30%
• carbidopa: 36%
• entacapone: 98%

Metabolites

• levodopa: dopamine, homovanillic acid
• carbidopa: alpha-methyl-3-methoxy-4-hydroxyphenyl propionic acid & alpha-methyl-3,4-dihydroxyphenylpropionic acid
• entacapone: cis-isomer

Elimination

• levodopa: urine: 80-85%
• carbidopa: 30% unchanged in urine
• entacapone: Urine (10%); feces (90%)