Levodopum, Carbidopum et Entacaponum

Description
An antiparkinsonian drug containing levodopa (dopamine precursor), carbidopa (DDC inhibitor, reduces peripheral levodopa metabolism), and entacapone (peripheral COMT inhibitor, slows down levodopa clearance from the bloodstream). Indications
Adult patients with Parkinson’s disease whose motor fluctuations at the end of the dose cycle are not stabilized by levodopa/dopadecarboxylase (DDC) inhibitors. Contraindications
Hypersensitivity to the active or excipient substance; severe hepatic impairment; closed-angle glaucoma; pheochromocytoma; concomitant use with non-selective MAO-A and MAO-B inhibitors (e.g., phenelzine, tranylcypromine); concomitant use with selective MAO-A and MAO-B inhibitors; history of malignant neuroleptic syndrome (MNS) and/or non-traumatic rhabdomyolysis. Dosage
Orally, one tablet with or without food; the whole tablet should be taken. The optimal daily dose is determined by titrating the levodopa dose for each patient. The most suitable daily dose is determined by prescribing one of the six possible strengths of tablets (50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg, 100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg, 150 mg/37.5 mg/200 mg, or 200 mg/50 mg/200 mg levodopa/carbidopa/entacapone). The maximum daily dose for strengths of 50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg, 100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg, and 150 mg/37.5 mg/200 mg is 10 tablets. Ten tablets of 150 mg/37.5 mg/200 mg strength correspond to 375 mg of carbidopa. Based on the daily dose of carbidopa, the highest recommended daily dose for the 200 mg/50 mg/200 mg strength is 7 tablets. For children. Not recommended for children under 18 years of age (insufficient data on safety and efficacy). For elderly patients. No need to adjust doses for these patients. In renal impairment. Caution is recommended when prescribing to patients with mild or moderate renal impairment (Child-Pugh class A and B). Dose reduction may be necessary (increased entacapone concentration during absorption and elimination phases). Contraindicated in severe renal impairment. In renal impairment. Renal impairment does not affect the pharmacokinetics of entacapone. There are no clinical study data on the pharmacokinetics of levodopa and carbidopa in patients with renal impairment, therefore, the drug should be cautiously prescribed to those with severe renal impairment, including those undergoing dialysis (sometimes requiring extended intervals between doses). Adverse reactions
Most common: dyskinesia (including choreiform, dystonic, or other involuntary movements), worsening of Parkinsonism, muscle twitching and blepharospasm, dizziness, dystonia, hyperkinesia, nausea, diarrhea, abdominal pain, dry mouth, constipation, vomiting, altered urine color, fatigue, increased sweating, falls, insomnia, hallucinations, confusion, nightmares, agitation, and other than myocardial infarction cases of ischemic heart disease. Others: irregular heart rhythm and/or palpitations, episodes of orthostatic hypotension, episodes of bradykinesia (on-off phenomenon), anorexia, weight loss, dizziness and somnolence, gastrointestinal bleeding, duodenal ulcer, hypertension, phlebitis, leukopenia, hemolytic or non-hemolytic anemia, thrombocytopenia, agranulocytosis, chest pain, dyspnea, and paresthesia, seizures, erythematous or maculopapular rash, urticaria, abnormal liver function test results. Disorders of the nervous system (ataxia, paresthesia, increased hand tremor, muscle weakness, trismus, activated latent Horner’s syndrome); eye disorders (diplopia, blurred vision, dilated pupils, oculogyric symptoms); gastrointestinal disorders: (metallic taste, drooling, dysphagia, teeth grinding, hiccup, diarrhea, colitis, flatulence, burning sensation on the tongue, hepatitis); renal and urinary disorders (urinary retention, incontinence, priapism); skin and subcutaneous tissue disorders (facial flushing, darkened sweat, altered skin, hair, beard, and nail color, hair loss); psychiatric disorders: (delusion, anxiety, euphoria, mental changes (including paranoid ideas and psychosis attacks), depression with suicidal tendencies or without, cognitive dysfunction). Pregnancy
There is insufficient data on the use of levodopa/carbidopa/entacapone combination in pregnant women. It should not be used during pregnancy unless the benefit to the mother outweighs the potential risk to the fetus. Breastfeeding
Levodopa enters breast milk, inhibiting lactation. Carbidopa and entacapone are excreted in animal milk, but it is unknown whether they enter human milk. The safety of levodopa, carbidopa, or entacapone for the infant is unknown. Women taking this medication cannot breastfeed their infant. Warnings
Not recommended for treating drug-induced extrapyramidal reactions. Caution is advised in patients with a history of myocardial infarction and residual atrial or ventricular arrhythmias, coronary heart disease, severe cardiovascular or pulmonary disease, bronchial asthma, kidney or endocrine disease, history of peptic ulcer, or a history of seizures. Patients should be closely monitored for possible mental changes, depression with suicidal tendencies; treat individuals with caution who have been diagnosed with or have a history of psychosis.Caution should be exercised when co-administering medications for psychosis that have a blocking effect on dopamine receptors, especially D2 receptor antagonists, due to the potential weakening of the treatment effect of Parkinson’s disease. Patients, particularly those taking antipsychotics, should be carefully monitored when their levodopa dose is suddenly reduced or discontinued. If it is necessary to switch the medication to a levodopa/DDK inhibitor without entacapone or to change other dopaminergic drugs, this should be done gradually (sometimes requiring an increase in the levodopa dose). The medication may cause orthostatic hypotension; it should be administered cautiously to those taking other medications that can cause orthostatic hypotension. Entacapone, when taken with levodopa, is associated with somnolence and sudden sleep attacks, so precautions must be taken when driving or operating machinery. Long-term users of the medication are recommended to periodically check liver, blood, cardiovascular, and kidney function. The medication contains sucrose, so patients with a rare inherited disorder – fructose intolerance, glucose and galactose malabsorption, or sucrase-isomaltase deficiency should not take this drug.

Source | Drug Guide | Lithuanian University of Health Sciences | Institute of Physiology and Pharmacology | Doctor of Medical Sciences Rimas Jankūnas, Doctor of Medical Sciences Arvydas Milašius | Clinic of Internal Diseases | Doctor of Medical Sciences Palmira Leišytė