Carbidopa-Levodopa-Entacapone (carbidopa/levodopa/entacapone)

The recommended dosage of entacapone is 200 mg administered with each levodopa-carbidopa dose up to a maximum of 8 times daily (1.6 g daily). Clinical experience with dosages exceeding 1.6 g daily is limited.

To optimize patient response, reductions in the daily levodopa dosage or frequency of administration may be necessary. In clinical studies, most patients (58%) who were receiving 800 mg or more of levodopa daily or who had moderate or severe dyskinesias before initiating entacapone therapy required a reduction in levodopa dosage; the average reduction in daily levodopa dosage was about 25%.

Levodopa and carbidopa are administered orally as fixed-combination or single-entity (carbidopa only) conventional tablets, orally disintegrating tablets, extended-release tablets, or extended-release capsules. Levodopa also is commercially available as a powder for oral inhalation. Carbidopa-levodopa enteral suspension is administered by direct intestinal infusion through a nasojejunal (NJ) tube or a percutaneous endoscopic gastrojejunostomy (PEG-J) tube.

In patients with moderate to severe motor fluctuations, better global improvement may be achieved in some patients when extended-release rather than conventional tablet preparations of carbidopa-levodopa are used. However, some studies have not found a substantial difference in ''off'' time between extended-release and immediate-release tablet preparations in such patients. In patients without motor fluctuations, the preparations were comparably effective but less frequent dosing was required with the extended-release preparation. Use of the extended-release capsule formulation of carbidopa-levodopa has been shown to improve ''off'' time compared with immediate-release preparations in patients with advanced parkinson disease. (See Absorption under Pharmacokinetics.)

Patients receiving other antiparkinsonian agents may continue taking these drugs while carbidopa-levodopa is administered; however, dosage adjustments of these drugs may be necessary.

Whenever a general anesthetic is required, levodopa may be continued as long as the patient is able to take fluids and medication orally. If therapy is interrupted, the patient should be observed for neuroleptic malignant syndrome and the usual daily dose may be given as soon as the patient can take oral medication.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Agents Affecting Growth Hormone/Macimorelin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

CLINICAL EFFECTS: Concurrent use of agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of macimorelin states concurrent use with agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test. Discontinue growth hormone products at least 1 week before administering the macimorelin diagnostic test. Sufficient washout time of drugs affecting growth hormone release prior to administration of macimorelin is recommended.(1) Agents affecting growth hormone include: - Drugs that directly affect the pituitary secretion of growth hormone (e.g. somatostatin, insulin, glucocorticoids, cyclooxygenase inhibitors) - Drugs that may transiently elevate growth hormone concentrations (e.g. clonidine, levodopa, insulin) - Drugs that may blunt the growth hormone response (e.g. muscarinic antagonists, anti-thyroid medications, growth hormone products)

DISCUSSION: Concurrent use of agents affecting growth hormone may impact the accuracy of the macimorelin diagnostic test.(1)

Carbidopa-Levodopa-Entacapone/Selected Maois

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Since monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the two major enzymes responsible for the metabolism of catecholamines, the combination of carbidopa-levodopa-entacapone and a non-selective MAOI may inhibit the majority of catecholamine metabolic pathways.(1-5)

CLINICAL EFFECTS: Concurrent administration of carbidopa-levodopa-entacapone with a non-selective MAOI may result in elevated levels of catecholamines, which may result in elevated heart rate and blood pressure.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of carbidopa-levodopa-entacapone states that concomitant use with a non-selective MAOI is contraindicated. Nonselective MAOIs should be discontinued at least 2 weeks prior to initiating therapy with carbidopa-levodopa-entacapone.(1) The US manufacturer of carbidopa-levodopa states that the concurrent use of nonselective MAO inhibitors is contraindicated. Carbidopa-levodopa may be administered with recommended dosages of selective MAO-B inhibitors.(2) The addition of a decarboxylase inhibitor to the combination of a non-selective MAO inhibitor and levodopa may minimize risk of adverse effects. Phentolamine has been effective in treating hypertension caused by this interaction. The Canadian(5) and UK(3) manufacturers of entacapone state that concomitant use of entacapone with either a non-selective MAOI or a selective MAO-A inhibitor and a MAO-B inhibitor is contraindicated. Nonselective MAOI should be discontinued at least 2 weeks prior to initiating entacapone therapy.(6)

DISCUSSION: Hypertensive reactions, flushing, and palpitations have been reported as a result of this interaction. This interaction may be possible for several weeks after the discontinuation of a MAO inhibitor. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the two major enzymes systems involved in the metabolism of catecholamines. Therefore, theoretically, the combination of either entacapone, tolcapone, or opicapone with a non-selective MAO inhibitor will result in inhibition of the majority of catecholamine metabolism pathways.(1-5) At daily oral doses of 10 mg, selegiline is primarily a selective MAO-B inhibitor; however, at higher doses, selegiline is capable of inhibiting MAO-A.(6) At dosages administered transdermally for the treatment of depression, selegiline is not selective for MAO-B.(7) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(8,9) Metaxalone is a weak inhibitor of MAO.(10,11)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Carbidopa-Levodopa-Entacapone/Linezolid

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Since monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the two major enzymes responsible for the metabolism of catecholamines, the combination of carbidopa-levodopa-entacapone and a non-selective MAOI may inhibit the majority of catecholamine metabolism pathways.(1-5) Linezolid is a weak, nonselective monoamine oxidase inhibitor (MAOI).(6)

CLINICAL EFFECTS: Concurrent administration of carbidopa-levodopa-entacapone with linezolid may result in elevated levels of catecholamines, which may result in elevated heart rate and blood pressure.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of carbidopa-levodopa-entacapone states that concomitant use with a non-selective MAOI is contraindicated. Nonselective MAOI should be discontinued at least 2 weeks prior to initiating therapy with carbidopa-levodopa-entacapone.(1) The US manufacturer of carbidopa-levodopa states that the concurrent use of nonselective MAO inhibitors is contraindicated. Carbidopa-levodopa may be administered with recommended dosages of selective MAO-B inhibitors.(2) The Canadian(5) and UK(3) manufacturers of entacapone state that concomitant use of either a non-selective MAOI or a selective MAO-A inhibitor with a selective MAO-B inhibitor with entacapone is contraindicated. Nonselective MAOI should be discontinued at least 2 weeks prior to initiating entacapone therapy. The manufacturer of linezolid does not contraindicate the use of adrenergic agents but states that they should not be coadministered unless the patient is closely monitored for potential increases in blood pressure.(6) If concurrent therapy is warranted, patients should be monitored closely for hypertensive crisis. The addition of a decarboxylase inhibitor to the combination of a non-selective MAO inhibitor and levodopa may minimize risk of adverse effects. Phentolamine has been effective in treating hypertension caused by this interaction.

DISCUSSION: Hypertensive reactions, flushing, and palpitations have been reported as a result of the interaction between levodopa and other MAO inhibitors. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the two major enzymes systems involved in the metabolism of catecholamines. Therefore, theoretically, the combination of either entacapone, tolcapone, or opicapone with a non-selective MAO inhibitor will result in inhibition of the majority of catecholamine metabolism pathways.(1-5) In a case report, an 89-year-old female with COPD, sick sinus syndrome, atrial fibrillation, hypertension, history of CVA, ischemic colitis, and Parkinson's disease on many medications including carbidopa-levodopa for 6 years took linezolid for 8 days and developed seizure-like activity. The patient was afebrile and normotensive, but was tachycardic, lethargic, agitated, and exhibited clonus on examination 2 days after linezolid was discontinued.(7)

Foslevodopa; Levodopa/Deutetrabenazine; Tetrabenazine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Deutetrabenazine and tetrabenazine antagonize the action of levodopa by inhibiting monoamine reuptake in the presynaptic terminals, thereby depleting dopamine in the central nervous system.(1-4) Foslevodopa is a prodrug of levodopa.(5)

CLINICAL EFFECTS: Concurrent administration with deutetrabenazine or tetrabenazine may result in decreased effectiveness of levodopa.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Recommendations for concurrent use of levodopa with tetrabenazine or deutetrabenazine vary in different regions. The Australian manufacturer of tetrabenazine states that concurrent use of levodopa is contraindicated. Levodopa should not be used concurrently with or within one day of discontinuing tetrabenazine.(1) The Australian and UK manufacturers of tetrabenazine state that tetrabenazine is contraindicated in patients with Parkinson's Disease.(1,2) Patients with levodopa-induced dyskinetic or choreiform movements should have their levodopa dose reduced rather than start concurrent therapy with tetrabenazine or deutetrabenazine.(3) If concurrent use is necessary, monitor patients for symptoms of parkinsonism. A dose reduction or discontinuation of tetrabenazine or deutetrabenazine may be required.(2-4)

DISCUSSION: Deutetrabenazine and tetrabenazine can antagonize the effect of levodopa.(1-4) Most manufacturers either recommend against concurrent use(2,3) or state that concurrent use is contraindicated.(4) The combination has been used in the treatment of levodopa-induced peak dose dyskinesias.(6)

Selected Dopamine Agonists/Selected Antiemetics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Selected dopamine agonists are used to treat neurologic conditions such as Parkinson Disease (PD)or restless legs syndrome (RLS), and endocrine disorders such as hyperprolactinemia by directly or indirectly increasing dopamine concentrations at dopamine-2 (D2) receptors in the central nervous system (CNS). Antiemetic agents which block CNS D2 receptors may counteract this effect.(1-5)

CLINICAL EFFECTS: The efficacy of the dopamine agonist may be decreased, leading to exacerbation of the disease being treated. In patients with Parkinson disease motor symptoms may worsen, increasing the risk for falls, dysphagia or aspiration.(5) Patients with other conditions such as restless legs syndrome may also experience symptom exacerbation due to this combination.

PREDISPOSING FACTORS: Patients with Parkinson or Diffuse Lewy Body (DLB) disease are particularly susceptible to adverse effects of dopamine blockade.

PATIENT MANAGEMENT: Reassess antiemetic therapy and use an antiemetic without dopamine (D2) blocking effects if possible. If clinically appropriate and available, consider the use of a 5HT3 blocker (e.g. ondansetron) or domperidone (not available in the US).(4) If concomitant treatment is needed, monitor for loss of efficacy for the disease being treated by the dopamine agonist (e.g. Parkinson disease, restless legs syndrome) and adjust medication(s) or dosage if needed.(1-4) Counsel patients to report symptoms of disease exacerbation.

DISCUSSION: Patients with Parkinson or DLB disease are particularly susceptible to adverse effects of dopamine blockade. The European Academy of Neurology guideline for late Parkinson disease states that metoclopramide, cinnarizine and prochlorperazine must be avoided. Ondansetron or domperidone(not available in the US) may be used for nausea and vomiting.(5) Prescribing information for dopamine agonists warn of the risk for disease exacerbation when dopamine blocking agents are co-prescribed.(1-4)

Selected Dopamine Agonists/Selected Antipsychotics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Selected dopamine agonists are used to treat neurologic conditions such as Parkinson Disease (PD)or restless legs syndrome, and endocrine disorders such as hyperprolactinemia by directly or indirectly increasing dopamine concentrations at D2 receptors in the central nervous system (CNS). Antipsychotic agents counteract this effect by blocking dopamine activity at CNS D2 receptors.(1-5)

CLINICAL EFFECTS: The efficacy of either agent may be decreased, leading to exacerbation of the disease being treated. In patients with Parkinson disease motor symptoms may worsen, increasing the risk for falls, dysphagia or aspiration.(4,7) Compared with Parkinson patients not receiving antipsychotic therapy, Parkinson patients receiving antipsychotics appear to have an increased mortality risk.(6) Patients with other conditions such as restless legs syndrome or a psychotic disorder may also experience symptom exacerbation due to this combination.

PREDISPOSING FACTORS: Patients with Parkinson or Diffuse Lewy Body (DLB) disease are particularly susceptible to adverse effects of dopamine blockade by antipsychotics.

PATIENT MANAGEMENT: Reassess the need for antipsychotic therapy. If psychosis or hallucinations are due to an antiparkinson agent, when possible consider reducing the dose or changing the antiparkinson agent before initiating antipsychotic therapy. In patients with PD and dementia, addition of a cholinesterase inhibitor (e.g. rivastigmine) may improve psychosis. If an antipsychotic is required, then an atypical antipsychotic should be used.(6,7) In patients with major psychotic disorders, consider reducing the dose, changing or stopping the dopamine agonist. The US manufacturer of ropinirole recommends treatment with dopamine agonists only if potential benefits outweigh risks.(1) The US manufacturer of entacapone states it should not ordinarily be used in patients with major psychotic disorders as entacapone may lead to an exacerbation of psychosis.(4)

DISCUSSION: An epidemiologic study evaluated 21,043 elderly patients with Parkinson disease to determine if recent initiation of a typical or atypical antipsychotic was associated with increased mortality. They found an adjusted odds ratio of 2.0 for death associated with atypical antipsychotics versus no antipsychotic They found an adjusted odds ratio of 2.4 for death associated with typical versus atypical antipsychotics. The authors noted the increased mortality found with typical antipsychotics supports current treatment recommendations to use atypical antipsychotic agents in patients with Parkinson disease.(6,7)

Selected Dopaminergic Agents/Slt Antipsychotics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Selected dopaminergic agents are used to treat neurologic conditions such as Parkinson Disease (PD) or restless legs syndrome, and endocrine disorders such as hyperprolactinemia by directly or indirectly increasing dopamine concentrations at D2 receptors in the central nervous system (CNS). Antipsychotic agents counteract this effect by blocking dopamine activity at CNS D2 receptors.(1-5)

CLINICAL EFFECTS: The efficacy of either agent may be decreased, leading to exacerbation of the disease being treated. In patients with Parkinson disease motor symptoms may worsen, increasing the risk for falls, dysphagia or aspiration.(4,7) Compared with Parkinson patients not receiving antipsychotic therapy, Parkinson patients receiving antipsychotics appear to have an increased mortality risk.(6) Patients with other conditions such as restless legs syndrome or a psychotic disorder may also experience symptom exacerbation due to this combination.

PREDISPOSING FACTORS: Patients with Parkinson or Diffuse Lewy Body (DLB) disease are particularly susceptible to adverse effects of dopamine blockade by antipsychotics.

PATIENT MANAGEMENT: Reassess the need for antipsychotic therapy. If psychosis or hallucinations are due to an antiparkinson agent, when possible consider reducing the dose or changing the antiparkinson agent before initiating antipsychotic therapy. In patients with PD and dementia, addition of a cholinesterase inhibitor (e.g. rivastigmine) may improve psychosis. If an antipsychotic is required, then an atypical antipsychotic should be used.(6,7) In patients with major psychotic disorders, consider reducing the dose, changing or stopping the dopaminergic agent. The US manufacturer of ropinirole recommends treatment with dopaminergic agents only if potential benefits outweigh risks.(1) The US manufacturer of entacapone states it should not ordinarily be used in patients with major psychotic disorders as entacapone may lead to an exacerbation of psychosis.(4)

DISCUSSION: An epidemiologic study evaluated 21,043 elderly patients with Parkinson disease to determine if recent initiation of a typical or atypical antipsychotic was associated with increased mortality. They found an adjusted odds ratio of 2.0 for death associated with atypical antipsychotics versus no antipsychotic They found an adjusted odds ratio of 2.4 for death associated with typical versus atypical antipsychotics. The authors noted the increased mortality found with typical antipsychotics supports current treatment recommendations to use atypical antipsychotic agents in patients with Parkinson disease.(6,7)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Amantadine; Foslevodopa; Levodopa/Bupropion

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Amantadine, levodopa, and bupropion have dopamine agonist effects. Toxicity may result from cumulative dopamine agonist effects.(1) Foslevodopa is a prodrug of levodopa.(2)

CLINICAL EFFECTS: Concurrent administration of amantadine/levodopa and bupropion may result in CNS toxicity, such as, restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use caution when amantadine/levodopa and bupropion are used concurrently. Monitor for signs of CNS toxicity, which may include restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness.(1)

DISCUSSION: CNS toxicity has been reported with concurrent administration of amantadine and bupropion. Three out of six nursing home residents administered concurrent bupropion and amantadine developed confusion, restlessness, agitation, gross motor tremors, ataxia, gait disturbance, dizziness, and vertigo. Two patients had severe symptoms and were hospitalized.(3) In a case report, bupropion (75 mg twice daily) was added to amantadine, haloperidol, and benztropine. The patient became disoriented and agitated, developed visual and auditory hallucinations, impaired attention and memory, a fluctuating level of awareness, and unsteady gait.(4)

Carbidopa-Levodopa-Entacapone/Rasagiline; Oral Selegiline

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Since MAOI's and COMT are the two major enzymes responsible for the metabolism of catecholamines, the combination of carbidopa-levodopa-entacapone and a non-selective MAOI may inhibit the majority of catecholamine metabolism pathways.(1-5)

CLINICAL EFFECTS: Concurrent administration of carbidopa-levodopa-entacapone with a non-selective MAOI may result in elevated levels of catecholamines, which may result in elevated heart rate and blood pressure.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of carbidopa-levodopa-entacapone states that concomitant use with a non-selective MAOI is contraindicated. Nonselective MAOI should be discontinued at least 2 weeks prior to initiating therapy with carbidopa-levodopa-entacapone. Concomitant use with MAO-B inhibitors or other standard medications for Parkinson's disease may be used with carbidopa-levodopa-entacapone; dose adjustments of one or both drugs may be required.(1) The US manufacturer of carbidopa-levodopa states that the concurrent use of nonselective MAO inhibitors is contraindicated. Carbidopa-levodopa may be administered with recommended dosages of selective MAO-B inhibitors.(2) The addition of a decarboxylase inhibitor to the combination of a non-selective MAO inhibitor and levodopa may minimize risk of adverse effects. Phentolamine has been effective in treating hypertension caused by this interaction. The Canadian(5) and UK(3) manufacturers of entacapone state that concomitant use of either a non-selective MAOI or a selective MAO-A inhibitor with a selective MAO-B inhibitor with entacapone is contraindicated. Nonselective MAOI should be discontinued at least 2 weeks prior to initiating entacapone therapy.(6) Therefore, carbidopa-levodopa-entacapone may be used with oral selegiline, provided that the daily dose of selegiline does not exceed 10 mg, and with rasagiline, provided that the daily dose of rasagiline does not exceed 1 mg, and that patients are not also receiving a selective MAO-A inhibitor.

DISCUSSION: Hypertensive reactions, flushing, and palpitations have been reported as a result of this interaction. This interaction may be possible for several weeks after the discontinuation of a MAO inhibitor. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) are the two major enzymes systems involved in the metabolism of catecholamines. Therefore, theoretically, the combination of either entacapone, tolcapone, or opicapone with a non-selective MAO inhibitor will result in inhibition of the majority of catecholamine metabolism pathways.(1-5) At daily oral doses of 10 mg, selegiline is primarily a selective MAO-B inhibitor; however, at higher doses, selegiline is capable of inhibiting MAO-A.(8) At dosages administered transdermally for the treatment of depression, selegiline is not selective for MAO-B.(9)

Entacapone/Oral Iron Supplements

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Entacapone may chelate with iron within the gastrointestinal tract, reducing the absorption of both drugs.

CLINICAL EFFECTS: Simultaneous administration of entacapone and orally administered iron may decrease the clinical effects of both medications.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Iron supplements should not be taken within 2-3 hours before or after entacapone to minimize the effects of this interaction.(1) Some multivitamin preparations that contain sufficient quantities of iron may interact and not be properly absorbed as well.

DISCUSSION: Entacapone may form chelates with iron in the gastrointestinal tract, and preparations should be taken at least 2-3 hours apart.(1) Although the impact on the body's iron stores is unknown, clinical studies showed decreasing serum iron concentrations with coadministration of entacapone.(2) In repeated dose toxicity studies, anemia was observed most likely due to the iron chelating properties of entacapone.(1) Prescribing information of entacapone/levodopa/carbidopa states chelation of entacapone with iron may decrease bioavailability of entacapone/levodopa/carbidopa.(3)

Entacapone; Opicapone/Comt-Metabolized Agents

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Entacapone and opicapone are selective and reversible inhibitors of catechol-O-methyltransferase (COMT) and drugs that are metabolized by COMT can not be fully metabolized when given with entacapone or opicapone.(1)

CLINICAL EFFECTS: COMT-metabolized agents can interact with entacapone or opicapone and may result in an increased heart rates, arrhythmias, or an excessive change in blood pressure.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of entacapone and opicapone recommend using caution when administering entacapone or opicapone and a COMT-metabolized agent regardless of the route of administration (including inhalation).(1-3)

DISCUSSION: In an interaction study, ventricular tachycardia was observed after epinephrine and entacapone administration.(1) Another study on the effect of entacapone given with isoproterenol and epinephrine concluded that entacapone may potentiate the chronotropic and arrhythmogenic effects of isoproterenol and epinephrine.(4)

Foslevodopa; Levodopa/Isoniazid

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Isoniazid inhibits dopa decarboxylase, which is responsible for the decarboxylation of levodopa to dopamine.(1) Foslevodopa is a prodrug of levodopa.(2,3)

CLINICAL EFFECTS: Concurrent administration with isoniazid may result in decreased dopamine and decreased effectiveness of levodopa.(1-2,4-5)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with isoniazid and levodopa or foslevodopa for worsening Parkinson's symptoms.(3) The dose of levodopa may need to be increased.(1)

DISCUSSION: In a case report, a 74-year-old woman with Lewy Body Dementia stable on levodopa started rifampin 450 mg, ethambutol 500 mg, and isoniazid 300 mg daily for tubercular pleurisy and subsequently developed dysphagia, which resolved after increasing her dose of levodopa.(1) In another case, a patient with idiopathic Parkinson's disease deteriorated after starting rifampin and isoniazid for pulmonary tuberculosis. Motor function test found that the patient's "on" period was 75% longer after stopping antitubercular therapy and levodopa area-under-curve (AUC) and maximum concentration (Cmax) were 37% and 33% higher, respectively, compared to values obtained during TB therapy.(4) In a study of 20 patients, isoniazid 290 mg given to Parkinson's patients on levodopa resulted in reduced levodopa-induced choreic dyskinesias but intolerable worsening of Parkinson's symptoms.(5)

Selected Dopamine Agonists/Select Atypical Antipsychotics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Selected dopamine agonists are used to treat neurologic conditions such as Parkinson Disease (PD) or restless legs syndrome, and endocrine disorders such as hyperprolactinemia by directly or indirectly increasing dopamine concentrations at D2 receptors in the central nervous system (CNS). Antipsychotic agents counteract this effect by blocking dopamine activity at CNS D2 receptors.(1-5)

CLINICAL EFFECTS: The efficacy of either agent may be decreased, leading to exacerbation of the disease being treated, e.g. Parkinson disease or a psychotic disorder. Dopamine agonists linked to this monograph are: bromocriptine, entacapone, levodopa, pergolide, pramipexole, ropinirole and rotigotine. Atypical antipsychotics linked to this monograph are: aripiprazole, asenapine, iloperidone, lumateperone, lurasidone, paliperidone, quetiapine, risperidone, ziprasidone and zotepine.

PREDISPOSING FACTORS: Patients with Parkinson or Diffuse Lewy Body (DLB) disease are particularly susceptible to adverse effects of dopamine blockade by antipsychotics.

PATIENT MANAGEMENT: Reassess the need for antipsychotic therapy. If psychosis or hallucinations are due to an antiparkinson agent, when possible consider reducing the dose or changing the antiparkinson agent before initiating antipsychotic therapy. In patients with PD and dementia, addition of a cholinesterase inhibitor (e.g. rivastigmine) may improve psychosis. If an antipsychotic is required, then an atypical antipsychotic should be used.(6,7) In patients with major psychotic disorders, consider reducing the dose, changing, or stopping the dopamine agonist. The US manufacturer of ropinirole recommends treatment with dopamine agonists only if potential benefits outweigh risks.(1) The US manufacturer of entacapone states it should not ordinarily be used in patients with major psychotic disorders as entacapone may lead to an exacerbation of psychosis.(4)

DISCUSSION: An epidemiologic study evaluated 21,043 elderly patients with Parkinson disease to determine if recent initiation of a typical or atypical antipsychotic was associated with increased mortality. They found an adjusted odds ratio of 2.0 for death associated with atypical antipsychotics versus no antipsychotic. They found an adjusted odds ratio of 2.4 for death associated with typical versus atypical antipsychotics. The authors noted the increased mortality found with typical antipsychotics supports current treatment recommendations to use atypical antipsychotic agents in patients with Parkinson disease.(6,7) Two clozapine trials showed significant improvement in psychosis without worsening of motor symptoms. In contrast, two olanzapine trials were associated with unacceptable worsening of motor symptoms. Risperidone has also been associated with motor worsening in case reports. Quetiapine evaluations have been conflicting with several small studies showing improvement in psychotic symptoms while a more rigorous trial showed no improvement.(6)

Known hypersensitivity to entacapone or any ingredient in the formulation.

• Angle-closure glaucoma

• Acute myocardial infarction
• Bronchospastic pulmonary disease
• Cardiac arrhythmia
• Depression
• Diarrhea
• Dyskinesia
• Gastrointestinal ulcer
• Impulse control disorder
• Peptic ulcer
• Psychotic disorder
• Pyridoxine deficiency
• Suicidal ideation

• Biliary obstruction
• Disease of liver
• Dyskinesia
• Hallucinations
• Malignant melanoma
• No disease contraindications
• Open angle glaucoma
• Orthostatic hypotension
• Peripheral neuropathy

Adverse effects occurring in 1% or more of patients receiving entacapone and more frequently than placebo include dyskinesia, nausea, hyperkinesia, diarrhea, urine discoloration, hypokinesia, dizziness, abdominal pain, constipation, fatigue, vomiting, back pain, dry mouth, dyspnea, increased sweating, anxiety, somnolence, dyspepsia, flatulence, purpura, asthenia, taste perversion, agitation, gastritis, GI disorder, and bacterial infection.

More Frequent

• Akathisia
• Dyskinesia
• Hallucinations
• Hyperkinesis
• Hypokinesia
• Orthostatic hypotension

Less Frequent

• Bacterial infection
• Blepharospasm
• Orthostatic hypotension
• Syncope

Rare or Very Rare

• Abnormal hepatic function tests
• Accidental fall
• Acute cognitive impairment
• Acute myocardial infarction
• Aggressive behavior
• Agranulocytosis
• Altered mental status
• Anemia
• Bullous dermatitis
• Cardiac arrhythmia
• Colitis
• Delirium
• Drug-induced psychosis
• Drug-induced psychosis
• Duodenal ulcer
• Extrapyramidal disease
• Fever
• Hemolytic anemia
• Hepatitis
• Hyperbilirubinemia
• Hypertension
• Hyperventilation
• IgA vasculitis
• Impulse control disorder
• Increased alanine transaminase
• Increased aspartate transaminase
• Leukopenia
• Neuroleptic malignant syndrome
• Ocular hypertension
• Oculogyric crisis
• Paranoid disorder
• Pleural effusions
• Priapism
• Pulmonary fibrosis
• Pulmonary infiltrates
• Pyridoxine-dependent seizure
• Retroperitoneal fibrosis
• Rhabdomyolysis
• Sudden onset of sleep
• Suicidal
• Suicidal ideation
• Thrombocytopenic disorder

More Frequent

• Acute abdominal pain
• Altered mental status
• Ataxia
• Constipation
• Constipation
• Diarrhea
• Dizziness
• Dyskinesia
• Fatigue
• Headache disorder
• Insomnia
• Nausea
• Nausea
• Symptoms of anxiety
• Urine discoloration
• Vomiting

Less Frequent

• Acquired dystonia
• Acute cognitive impairment
• Agitation
• Anorexia
• Back pain
• Blurred vision
• Depression
• Diarrhea
• Dizziness
• Dream disorder
• Drowsy
• Dysgeusia
• Dyspepsia
• Dyspepsia
• Dyspnea
• Fatigue
• Flatulence
• Flushing
• Gastritis
• General weakness
• Hyperhidrosis
• Muscle fasciculation
• Peripheral edema
• Peripheral neuropathy
• Purpura
• Symptoms of anxiety
• Urine discoloration
• Vomiting
• Xerostomia
• Xerostomia

Rare or Very Rare

• Acquired horner syndrome
• Acute abdominal pain
• Alopecia
• Anticholinergic toxicity
• Bruxism
• Cough
• Diplopia
• Drowsy
• Drug-induced hot flash
• Dysgeusia
• Dysphagia
• Edema
• Euphoria
• Flatulence
• Gastrointestinal irritation
• Hallucinations
• Hiccups
• Hoarseness
• Hyperhidrosis
• Hypoesthesia
• Impulse control disorder
• Increased libido
• Leg pain
• Malaise
• Memory impairment
• Nervousness
• Phlebitis
• Pyridoxine deficiency
• Sialorrhea
• Sore throat
• Sudden onset of sleep
• Syncope
• Trismus
• Urinary incontinence
• Urinary retention
• Weight gain
• Weight loss

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Safety and effectiveness of entacapone have not been established in pediatric patients.

In animal reproduction studies in which entacapone was administered to pregnant rats and rabbits during the period of organogenesis, no evidence of teratogenicity was observed; however, there was an increased frequency of abortions, resorptions, decreased fetal weights, and fetal variations. When the drug was administered to female rats prior to mating and during early gestation, an increased incidence of fetal eye anomalies was observed; exposure to the drug during later stages of gestation and throughout lactation produced no evidence of developmental impairment in the offspring.

Entacapone has not been studied in pregnant women; therefore, the drug should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.

There are no adequate and well-controlled studies of levodopa and carbidopa in pregnant women. Reproduction studies in rodents using levodopa and carbidopa at dosages approximately 5 and 2 times greater than the maximum human dosage, respectively, have shown adverse effects on fetal and postnatal growth and viability, and studies in rabbits using the drug alone or in conjunction with carbidopa have shown visceral and skeletal malformations. Levodopa and carbidopa should be administered to pregnant women or women who might become pregnant only when the benefits to the mother outweigh the possible risks to the mother and fetus.

Levodopa is distributed into human milk. Carbidopa is distributed into milk in rats; it is not known whether carbidopa is distributed into human milk. Levodopa-carbidopa should be used with caution in nursing women. The known benefits of breast-feeding should be considered along with the mother's clinical need for the drug and any potential adverse effects on the infant from the drug or underlying maternal condition.

Entacapone is distributed into milk in rats; caution is advised if the drug is used in nursing women.

No substantial differences in safety or pharmacokinetics of entacapone have been observed relative to younger adults.