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  • CLASSES

    Anti-Parkinson Agents, Dopamine Precursors

    DEA CLASS

    Rx

    DESCRIPTION

    Aromatic amine that is metabolized to dopamine
    First-line oral treatment option in combination with carbidopa for motor symptoms in Parkinson's disease
    Available for oral inhalation for "as needed" use for 'off' episodes in Parkinson's patients receiving levodopa/carbidopa

    COMMON BRAND NAMES

    INBRIJA

    HOW SUPPLIED

    INBRIJA Respiratory (Inhalation) Pwd: 42mg

    DOSAGE & INDICATIONS

    For the treatment of Parkinson's disease or parkinsonism.
    For use as intermittent treatment for 'off' episodes associated with Parkinson's disease.
    Inhalation dosage
    Adults

    The contents of 2 capsules (42 mg per capsule for a total of 84 mg) inhaled orally with the provided inhaler as needed for 'off' symptoms up to 5 times daily. The dose should be taken when symptoms of an 'off' period start to return. DO NOT swallow the capsules; only use with the inhaler provided by the manufacturer. Max: 420 mg/day inhaled.

    Oral dosage
    Adults

    Initially, 500 mg to 1 gram PO, divided into 2 or more doses with food. The total daily dose is then gradually increased in increments less than or equal to 750 mg every 3 to 7 days, as tolerated. The usual optimal therapeutic dosage is less than or equal to 8 grams/day PO. Rarely a patient may be given more than 8 grams/day if carefully titrated. The optimal daily dose of levodopa (i.e., the dose producing maximal improvement of symptoms with tolerable side effects) must be determined and carefully titrated for each individual patient. In some patients, a significant therapeutic response may not be obtained until after 6 months of treatment. If carbidopa will be added to a patient who has previously been receiving levodopa monotherapy, the initial daily dosage of levodopa should be 20% to 25% or less of the previous daily levodopa amount.

    MAXIMUM DOSAGE

    Adults

    Generally, 8 grams/day PO; 420 mg/day via oral inhalation.

    Geriatric

    Generally, 8 grams/day PO; 420 mg/day via oral inhalation.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Administer orally with 6 to 8 ounces of water at least 30 minutes before eating or 1 hour after meals to maximize absorption.
    Levodopa may be taken with a small non-protein snack, such as fruit or a cracker, to avoid nausea. Administering with food may decrease absorption.

    Inhalation Administration

    Oral inhalation powder (capsules for oral inhalation; i.e., Inbrija)
    Each carton contains capsules in foil blister strips and 1 inhaler.
    The capsules are for oral inhalation using the manufacturer supplied inhaler device only. Do NOT swallow the capsules. Always use the new inhaler in the new carton. Do not save or use inhalers from previous cartons.
    Healthcare providers should instruct the patient on proper use of the inhaler device.
    Ensure hands are clean and dry and find a clean, dry surface to gather supplies and prepare dose. Check the expiration date and discard any expired product.
    Inhaler preparation:
    Remove the blue cap by pulling it straight off of the inhaler and place the cap to the side for later use.
    Twist and pull off the mouthpiece to separate it from the handle.
    Capsule preparation:
    Just prior to use, remove 1 capsule from packaging by carefully peeling back the foil.
    Do NOT try to push the capsule through the back of the foil package. Only remove 1 capsule at a time.
    Discard any capsule that looks crushed, damaged, or wet.
    Repeat instructions for the second capsule after administration of the first capsule.
    Preparation of capsule with inhaler:
    Hold the inhaler upright using the handle.
    Drop 1 capsule into the opening of the capsule chamber. Do not load 2 capsules at the same time.
    Line up the white arrows on the handle and mouthpiece.
    Firmly push the mouthpiece and handle together until you hear a "click". This punctures the capsule.
    Release the mouthpiece, which will spring back and stay attached. The inhaler is now ready to use.
    Do not push the handle and mouthpiece together more than 1 time since the capsule may become damaged and the full dose may not be received.
    If the capsule becomes damaged, discard it in the trash and begin with a new capsule.
    Ensure the mouthpiece is securely attached and will not fall off before taking the dose.
    Dose administration (patient instructions):
    Stand or sit with your head and chest upright.
    Hold the inhaler level and away from the mouth.
    Breathe out completely. Do NOT breathe into the mouthpiece.
    While keeping the inhaler level, close your lips firmly around the mouthpiece.
    Take in a deep, comfortable breath until your lungs feel full. This normally takes several seconds.
    As you breathe in, you will hear and feel the capsule "whirl" (spin). The whirl means the inhaler is working.
    If you cough or stop inhaling the dose, start again using the same capsule.
    After inhaling the dose, remove inhaler from your mouth and hold your breath for 5 seconds, then breathe out.
    Twist and pull off the mouthpiece and take out the used capsule.
    Repeat steps for second capsule.
    Capsule disposition: After each use, discard the used capsules in the trash. Do NOT store capsules in the inhaler for future use.
    Inhaler disposition: Ensure there are no capsules in the inhaler before storing for the next use. Attach the mouthpiece to the handle by pushing until you hear a "click". Attach the blue cap over the mouthpiece. Store for next use. Discard the inhaler after all of the capsules in the package have been used.
    Cleaning the inhaler: It is normal for some powder to remain on the inhaler. Cleaning the inhaler is not necessary; however, a dry cotton swab or a dry tissue may be used to wipe the inside or outside of the mouthpiece.
    Refer to the Instructions for Use section of the product labeling for detailed visual aids which accompany the written instructions.

    STORAGE

    INBRIJA:
    - Product should always be stored in the blister and only removed immediately before use
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Abrupt discontinuation, surgery

    Avoid abrupt discontinuation of oral or oral inhalation levodopa therapy. Sporadic cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been associated with dose reductions and withdrawal of levodopa or other medications with dopaminergic properties, and may be life-threatening. Therefore, patients should be observed carefully when the dosage of levodopa is reduced abruptly or discontinued, especially if the patient is receiving antipsychotics. Manifestations of NMS include hyperthermia, tachycardia, muscular rigidity, confusion, diaphoresis, tachypnea, and increases in serum creatinine levels. The early diagnosis of this condition is important for the appropriate management of these patients, which includes intensive medical monitoring and management. Prior to general anesthesia and surgery, levodopa may be continued as long as the patient is permitted to take oral medication. If levodopa-based therapy is interrupted temporarily, the patient should be observed for signs of neuroleptic malignant syndrome, and the usual dosage should be administered as soon as the patient is able to take oral medication. Cases of neuroleptic malignant syndrome have been reported post-surgery so close monitoring is warranted. In addition, some patients receiving levodopa have experienced postoperative bleeding episodes, so hematological studies are recommended for all patients who undergo surgery while receiving this drug.

    Cardiac arrhythmias, cardiac disease, myocardial infarction

    Levodopa should be administered with extreme caution to patients with cardiac disease. Levodopa should be used with caution in patients a history of myocardial infarction who have residual cardiac arrhythmias (i.e., atrial, nodal, or ventricular arrhythmias). Cardiac monitoring in a facility with provisions for intensive cardiac care is recommended during initial titration of levodopa in patients with significant cardiac disease.

    Asthma, chronic obstructive pulmonary disease (COPD), pulmonary disease

    Because levodopa may alter breathing patterns or respiratory rates in some patients, it should be used under careful observation in patients with severe pulmonary disease. Levodopa for oral inhalation is not recommended in patients with asthma, chronic obstructive pulmonary disease (COPD), or other chronic underlying lung diseases because of the risk of bronchospasm.[63854] Oral levodopa should be used with caution in patients with a history of bronchial asthma and COPD who are receiving sympathomimetic therapies; levodopa has additional sympathomimetic effects.

    Hepatic disease, renal disease

    Levodopa should be used with caution in patients with renal disease or hepatic disease; the drug has not been formally evaluated in these populations. Periodic evaluations of hepatic and renal function are usually recommended during prolonged treatment with levodopa in combination with carbidopa.

    Peptic ulcer disease

    Levodopa may increase the risk of upper GI hemorrhage in patients with a history of active peptic ulcer disease; use with extreme caution in such patients.

    Depression, mental status changes, psychosis, schizophrenia, suicidal ideation

    Because of the risk of exacerbating psychosis and reports of hallucinations occurring during treatment with levodopa, patients with a psychotic disorder (e.g., schizophrenia) should generally not be treated with levodopa. Hallucinations that occur during levodopa therapy may be responsive to a reduction in levodopa dosage. Other potential mental status changes include confusion, paranoid ideation, disorientation, aggression, agitation, and delirium. All patients receiving levodopa should also be monitored closely for signs of depression and suicidal ideation.

    Diabetes mellitus

    Patients with diabetes mellitus should be monitored during levodopa therapy. Alterations in blood glucose may occur in some individuals as a result of the sympathomimetic effects of levodopa. Levodopa may cause a false-positive reaction for urinary ketone bodies when a test tape is used for determination of ketonuria. False-negative tests may result with use of glucose-oxidase methods of testing for glucosuria.

    Closed-angle glaucoma

    Oral levodopa (e.g., Sinemet) is contraindicated in patients with closed-angle glaucoma, but may be used in patients with open-angle glaucoma if intraocular pressure is closely monitored and controlled. Levodopa for oral inhalation (e.g., Inbrija) may cause an increase in intraocular pressure in patients with glaucoma, and patients should be monitored for increased intraocular pressure during treatment.

    Melanoma

    Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk is due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear. Patients and providers are advised to monitor for melanoma frequently and on a regular basis when using levodopa for any indication. Ideally, periodic skin examination should be performed by appropriately qualified individuals (e.g., dermatologists).

    Pregnancy

    Levodopa should be used in pregnancy only if the potential benefit outweighs the potential risk to the fetus. There are no adequate or well-controlled studies regarding the developmental risks to the fetus from levodopa use during human pregnancy. Levodopa/carbidopa therapy has been shown to be developmentally toxic in animal studies. Levodopa crosses the placenta in humans and reaches levels in the fetus comparable to maternal blood, although pregnancy outcomes have been primarily unremarkable. Two miscarriages were reported in the first trimester during use of carbidopa/levodopa, and one infant exposed to levodopa in utero was reported to have osteomalacia. One case of neonatal seizure occurred after use of bromocriptine plus carbidopa/levodopa/entacapone during pregnancy. A separate case describes a patient who became pregnant on 2 separate occasions while receiving levodopa and cabergoline for Parkinson's disease. The medications were continued throughout the pregnancies. There were no fetal complications; however, C-section was required in the second birth due to placental abruption. Maternal complications reported in three pregnancies during use of levodopa in combination with carbidopa included first trimester vaginal bleeding, third trimester nausea and vomiting, depression, and preeclampsia. The effects of levodopa in labor and delivery are unknown.

    Breast-feeding

    Excretion of levodopa into breast milk has been reported, and caution is advisable in breast-feeding mothers.[48681] [63854] Because levodopa can inhibit prolactin secretion, interference with proper lactation is possible; however, there are limited data about this potential in lactating women.[48681] [63854] Partial to complete suppression of lactation has been observed in female patients given levodopa for galactorrhea.[48683] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.[48681] [63854] In one case report of a breast-feeding mother with Parkinson's disease receiving sustained-release carbidopa/levodopa 50/200 mg 4 times daily, peak levels of levodopa in milk occurred 3 hours after a dose and returned to baseline after 6 hours. After receiving the same dose of the immediate-release (IR) formulation, similar results were observed, with the exception of higher milk: plasma ratios with the IR product (0.32 vs. 0.28). The infant ingested 0.127 mg and 0.181 mg of levodopa after maternal intake of the sustained-release and immediate-release products, respectively. It was estimated that the infant received an average of 0.3% of the maternal weight-adjusted dosage of the sustained release product and 0.5% of the maternal weight-adjusted dose of the immediate-release product. No adverse effects were observed in her infant, whose development was normal at 2 years of age.[48662] If levodopa must be administered during breast-feeding, the infant should be monitored for commonly encountered adverse effects associated with dopaminergic therapy including dyskinesias, insomnia, sedation, nausea, and constipation.

    Children, infants

    Levodopa oral inhalation has not been studied in adolescents, children, and infants under 18 years of age. Oral formulas have not been adequately studied for safety and efficacy in children and adolescents less than 18 years of age, though off-label use is rarely described in the literature. This drug is not indicated in infants. Juvenile onset Parkinson's disease is very rare.

    Laboratory test interference, pheochromocytoma

    Rarely, falsely diagnosed pheochromocytoma has been reported in patients receiving levodopa due to a laboratory test interference. Caution should be exercised with interpreting the plasma and urine levels of catecholamines and catecholamine metabolites in patients on levodopa.

    Geriatric

    Levodopa can cause mental status changes or other adverse CNS effects. Although no overall meaningful differences in safety or effectiveness were observed between geriatric and younger adults in clinical trials of levodopa combination products, a greater sensitivity of some geriatric patients to adverse CNS effects associated with levodopa cannot be ruled out. Therefore, careful monitoring is advisable for behavioral or mental status changes including depression, suicidal ideation, confusion, hallucinations, and delirium. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, antiparkinson medications may cause significant confusion, restlessness, delirium, dyskinesia, nausea, dizziness, hallucinations, and agitation. In addition, there is an increased risk of postural hypotension and falls, particularly during concurrent use of antihypertensive medications.

    Driving or operating machinery

    Sudden sleep onset has been reported in patient receiving levodopa. Some incidents have occurred while the patient was driving or performing other potentially hazardous activities. In some cases excessive drowsiness due to levodopa has resulted in auto accidents or other harmful events in the course of daily living. Sudden sleep onset has occurred more than one year after the initiation of treatment in some cases. Prior to initiating treatment with levodopa, patients should be advised of the potential to develop somnolence and specifically asked about factors that may increase the risk of experiencing such an event such as concomitant use of sedating medications (coadministration with other CNS depressants), ethanol ingestion, or the presence of sleep disorders (e.g., narcolepsy, sleep apnea). Patients should be cautioned against driving or operating machinery, or performing other tasks that require alertness, until they gauge how levodopa affects their motor performance. Reassessment for drowsiness or oversedation is necessary throughout levodopa therapy because patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), consider discontinuation of levodopa. If a decision is made to continue the drug, patients should be advised to not drive and to avoid other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

    Impulse control symptoms

    Some patients receiving medications that increase dopaminergic tone have reported intense and uncontrollable urges to gamble, increased sexual urges, or other intense urges. Causality due to dopaminergic agents has not been established; however, in some cases the urges stopped after the dose was reduced or the drug was discontinued. Practitioners should inquire periodically about new or worsening impulse control symptoms in patients receiving levodopa. Likewise, patients should be instructed to report such changes while receiving levodopa. Dose reduction or discontinuation should be considered in those who experience these effects.

    MAOI therapy

    Concomitant use of non-selective monoamine oxidase inhibitor therapy (MAOI therapy) with levodopa can result in hypertensive crisis, and simultaneous use of these agents is contraindicated. Non-selective MAOIs should be discontinued at least 2 weeks before initiation of oral or oral inhalation levodopa therapy.

    ADVERSE REACTIONS

    Severe

    akinesia / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    peptic ulcer / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    ocular hypertension / Delayed / Incidence not known
    neuroleptic malignant syndrome-like symptoms / Delayed / Incidence not known
    skin cancer / Delayed / Incidence not known

    Moderate

    skin laceration / Delayed / 2.0-2.0
    chest pain (unspecified) / Early / 0-2.0
    dyskinesia / Delayed / 10.0
    myoclonia / Delayed / Incidence not known
    dystonic reaction / Delayed / Incidence not known
    involuntary movements / Delayed / Incidence not known
    akathisia / Delayed / Incidence not known
    trismus / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    depression / Delayed / Incidence not known
    euphoria / Early / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    delirium / Early / Incidence not known
    confusion / Early / Incidence not known
    psychosis / Early / Incidence not known
    ataxia / Delayed / Incidence not known
    memory impairment / Delayed / Incidence not known
    constipation / Delayed / Incidence not known
    dysphagia / Delayed / Incidence not known
    teeth grinding (bruxism) / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    glycosuria / Early / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    phlebitis / Rapid / Incidence not known
    palpitations / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    orthostatic hypotension / Delayed / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    dyspnea / Early / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    urinary retention / Early / Incidence not known
    priapism / Early / Incidence not known
    urinary incontinence / Early / Incidence not known
    hematuria / Delayed / Incidence not known
    sudden sleep onset / Delayed / Incidence not known
    impulse control symptoms / Delayed / Incidence not known
    hot flashes / Early / Incidence not known
    edema / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    blepharospasm / Early / Incidence not known

    Mild

    cough / Delayed / 15.0-15.0
    infection / Delayed / 0-6.0
    nausea / Early / 5.0-5.0
    vomiting / Early / 3.0-3.0
    pharyngitis / Delayed / 3.0-3.0
    headache / Early / 2.0-2.0
    insomnia / Early / 2.0-2.0
    pruritus / Rapid / Incidence not known
    purpura / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    flushing / Rapid / Incidence not known
    rash / Early / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    abnormal dreams / Early / Incidence not known
    tremor / Early / Incidence not known
    paranoia / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    anxiety / Delayed / Incidence not known
    restlessness / Early / Incidence not known
    agitation / Early / Incidence not known
    nightmares / Early / Incidence not known
    dizziness / Early / Incidence not known
    hiccups / Early / Incidence not known
    diarrhea / Early / Incidence not known
    dyspepsia / Early / Incidence not known
    weight gain / Delayed / Incidence not known
    xerostomia / Early / Incidence not known
    weight loss / Delayed / Incidence not known
    anorexia / Delayed / Incidence not known
    hypersalivation / Early / Incidence not known
    dysgeusia / Early / Incidence not known
    flatulence / Early / Incidence not known
    syncope / Early / Incidence not known
    urine discoloration / Early / Incidence not known
    hoarseness / Early / Incidence not known
    vitamin B6 deficiency / Delayed / Incidence not known
    increased urinary frequency / Early / Incidence not known
    drowsiness / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    fatigue / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    malaise / Early / Incidence not known
    muscle cramps / Delayed / Incidence not known
    back pain / Delayed / Incidence not known
    mydriasis / Early / Incidence not known
    diplopia / Early / Incidence not known

    DRUG INTERACTIONS

    Alfentanil: (Major) Prior to general anesthesia, levodopa may be continued as long as the patient is permitted to take oral medication. If levodopa-based therapy is interrupted temporarily, the usual daily dosage may be reinstituted or titrated upward to the normal dosage as soon as the patient is able to take oral medications. The patient should be observed for symptoms resembling neuroleptic malignant syndrome, and the usual regimen should be administered as soon as the patient is able to take oral medication.
    Amantadine: (Minor) Amantadine can increase the efficiency of levodopa by its action on central nerve terminals.
    Amoxapine: (Moderate) Amoxapine exhibits antimuscarinic activity and can decrease gastric motility, decreasing the bioavailability of levodopa. In addition, severe hypertension occurred in a limited number of patients who received levodopa in combination with a tricyclic antidepressant.
    Amphetamine; Dextroamphetamine Salts: (Major) Levodopa, due to its conversion to dopamine, may increase the risk of developing amphetamine-induced cardiac arrhythmias; dosage reductions of amphetamines are recommended if the two agents are used concurrently.
    Angiotensin II receptor antagonists: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Angiotensin-converting enzyme inhibitors: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Apomorphine: (Minor) Concurrent administration of apomorphine and levodopa may significantly reduce the threshold levodopa concentration necessary for an improved motor response, leading to an increased duration of effect without a change in the maximal response to levodopa therapy. Monitor the patient for any needed dosage adjustments.
    Atropine: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added. (Minor) Through its central antimuscarinic actions, hyoscyamine can potentiate the dopaminergic effects of levodopa. Clinicians should be ready to decrease doses of levodopa if hyoscyamine is added.
    Atropine; Difenoxin: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
    Atropine; Diphenoxylate: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
    Atropine; Edrophonium: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added. (Minor) Through its central antimuscarinic actions, hyoscyamine can potentiate the dopaminergic effects of levodopa. Clinicians should be ready to decrease doses of levodopa if hyoscyamine is added.
    atypical antipsychotic: (Moderate) Levodopa is a potent dopamine-receptor agonist. Dopamine-receptor antagonists, including the atypical antipsychotics, may reduce the effects of levodopa. In general, the atypical antipsychotics are less likely to interfere with antiparkinson treatments than traditional antipsychotic agents. Monitor for diminished effectiveness of the antiparkinson treatments, for movement disorders, and for unusual changes in moods or behavior. Certain atypical antipsychotics, such as quetiapine or pimavanserin, may be preferable to other antipsychotics in these patients.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
    Belladonna; Opium: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Minor) Through its central antimuscarinic actions, hyoscyamine can potentiate the dopaminergic effects of levodopa. Clinicians should be ready to decrease doses of levodopa if hyoscyamine is added.
    Benzphetamine: (Major) Levodopa, due to its conversion to dopamine, may increase the risk of developing amphetamine-induced cardiac arrhythmias; dosage reductions or discontinuation of benzphetamine is recommended if the two agents are used concurrently.
    Benztropine: (Minor) Through its central antimuscarinic actions, antimuscarinics such as benztropine can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if benztropine is added.
    Beta-blockers: (Moderate) Concomitant use of beta-blockers with levodopa can result in additive hypotensive effects.
    Bupropion: (Major) Use bupropion cautiously in patients taking levodopa or combination drugs containing levodopa (e.g., carbidopa; levodopa and carbidopa; levodopa; entacapone). Both drugs are dopamine agonists; cumulative effects may result in central nervous system (CNS) toxicity. Adverse reactions reported with coadministration have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. If levodopa is used concurrently, low initial dosing and slow dosage titration of bupropion may be warranted.
    Bupropion; Naltrexone: (Major) Use bupropion cautiously in patients taking levodopa or combination drugs containing levodopa (e.g., carbidopa; levodopa and carbidopa; levodopa; entacapone). Both drugs are dopamine agonists; cumulative effects may result in central nervous system (CNS) toxicity. Adverse reactions reported with coadministration have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. If levodopa is used concurrently, low initial dosing and slow dosage titration of bupropion may be warranted.
    Cabergoline: (Minor) Cabergoline and levodopa both increase dopaminergic function centrally. Cabergoline is used as an adjunct to levodopa/carbidopa therapy in patients with Parkinson's disease experiencing motor fluctuations. Although this combination appears safe and effective overall, additive neurologic effects are possible. Hallucinations have been reported with the concurrent use of cabergoline and levodopa.
    Calcium-channel blockers: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Central-acting adrenergic agents: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with levodopa should generally be avoided because of the possibility of additive sedative effects. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
    Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with levodopa should generally be avoided because of the possibility of additive sedative effects. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
    Chlorpromazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Chlorthalidone; Clonidine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Clonidine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Cocaine: (Major) Concomitant use of cocaine with levodopa (including carbidopa; levodopa and carbidopa; levodopa; entacapone) can result in an increase in the risk of developing cardiac arrhythmias. Levodopa should be used cautiously in patients who are known users of cocaine. Conversely, electrocardiographic monitoring should be considered when using cocaine in patients receiving levodopa.
    Codeine; Phenylephrine; Promethazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Codeine; Promethazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Dacarbazine, DTIC: (Moderate) Levodopa response may be decreased during chemotherapy with dacarbazine, DTIC. If dacarbazine is used in a patient stabilized on levodopa therapy, practitioners may wish to be alert for needed adjustments in the levodopa regimen to maintain patient status.
    Darifenacin: (Minor) Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. Antimuscarinics, by slowing GI transit, may also decrease levodopa bioavailability; however, this mechanism appears to be of modest clinical significance. Antimuscarinic agents targeted specifically for urinary incontinence may be less likely to produce pronounced effects on levodopa response than those with more pronounced systemic action.
    Dexmethylphenidate: (Moderate) Increased dopaminergic effects may occur during coadministration of dexmethylphenidate, an inhibitor of dopamine reuptake, and medications that increase dopaminergic activity such as levodopa. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible.
    Dextromethorphan; Promethazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Dicyclomine: (Minor) Anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
    Doxazosin: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Droperidol: (Major) Droperidol, a butyrophenone derivative, is a dopamine D2 receptor antagonist and thus, may reduce the therapeutic effects of levodopa, which is an agonist at dopamine D2 receptors. Avoidance of droperidol use in a patient with Parkinson's disease may be advisable unless the benefit of droperidol outweighs the risk of CNS depressive effects and decreased therapeutic response to dopamine agonists.
    Enflurane: (Major) If administered before halogenated anesthetics, levodopa without concomitant use of a decarboxylase inhibitor has been associated with cardiac arrhythmias. This interaction is presumably due to the levodopa-induced increases in plasma dopamine. Levodopa single-agent therapy should be discontinued 6 to 8 hours before administering halogenated anesthetics. Otherwise, when general anesthesia is required, levodopa may be continued as long as the patient is permitted to take oral medication. Patients should be observed for signs of neuroleptic malignant syndrome while therapy is interrupted, and the usual levodopa regimen should be administered as soon as the patient is able to take oral medication.
    Eplerenone: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Epoprostenol: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Esketamine: (Major) Because of the possibility of additive sedative effects, caution is advisable during concurrent use of dopaminergic agents, such as levodopa, and CNS depressants, such as esketamine. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa. Administration of iron salts, including polysaccharide-iron complex, should be separated from levodopa by at least 2 hours.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa. Administration of iron salts, including polysaccharide-iron complex, should be separated from levodopa by at least 2 hours.
    Fluphenazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Food: (Major) Foods with a high protein content may interfere with the absorption of levodopa. It has been recommended to take levodopa at least 30 minutes before eating or one hour after meals. (Major) Patients with Parkinson's disease should avoid foods high in fat around the time of taking carbidopa; levodopa. These foods may delay gastric emptying, which can decrease and delay the absorption of levodopa. (Major) Patients with Parkinson's disease should avoid foods high in fiber around the time of taking carbidopa; levodopa. These foods may delay gastric emptying, which can decrease and delay the absorption of levodopa.
    Fosphenytoin: (Moderate) Phenytoin or fosphenytoin can possibly interfere with the effects of levodopa; the mechanism of the interaction has not been established. The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin. Monitor carefully for loss of therapeutic response.
    Furazolidone: (Major) Concomitant use of levodopa and drugs with monoamine oxidase inhibitor activity, such as furazolidone, can result in hypertensive crisis. Simultaneous use of these agents should be avoided if possible.
    Glycopyrrolate: (Moderate) Coadministration of glycopyrrolate with levodopa may decrease levodopa serum concentrations. If coadministration is necessary, monitor clinical response to levodopa and increase levodopa dose accordingly.
    Glycopyrrolate; Formoterol: (Moderate) Coadministration of glycopyrrolate with levodopa may decrease levodopa serum concentrations. If coadministration is necessary, monitor clinical response to levodopa and increase levodopa dose accordingly.
    Guanabenz: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Guanfacine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Haloperidol: (Major) Antipsychotic agents may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain. Haloperidol should be avoided during therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments.
    Halothane: (Major) The use of levodopa with halothane may enhance cardiac adverse effects of halothane. This interaction is presumably due to the levodopa-induced increases in plasma dopamine. Levodopa single-agent therapy should be discontinued 6 to 8 hours before administering halogenated anesthetics. Otherwise, when general anesthetics are required, levodopa may be continued as long as the patient is permitted to take oral medication. Patients should be observed for signs of neuroleptic malignant syndrome while therapy is interrupted, and the usual levodopa regimen should be administered as soon as the patient is able to take oral medication.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Hyoscyamine: (Minor) Through its central antimuscarinic actions, hyoscyamine can potentiate the dopaminergic effects of levodopa. Clinicians should be ready to decrease doses of levodopa if hyoscyamine is added.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Minor) Through its central antimuscarinic actions, hyoscyamine can potentiate the dopaminergic effects of levodopa. Clinicians should be ready to decrease doses of levodopa if hyoscyamine is added.
    Iloprost: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Indacaterol; Glycopyrrolate: (Moderate) Coadministration of glycopyrrolate with levodopa may decrease levodopa serum concentrations. If coadministration is necessary, monitor clinical response to levodopa and increase levodopa dose accordingly.
    Iron Salts: (Major) Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa. Administration of iron salts, including polysaccharide-iron complex, should be separated from levodopa by at least 2 hours.
    Iron: (Major) Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa. Administration of iron salts, including polysaccharide-iron complex, should be separated from levodopa by at least 2 hours.
    Isocarboxazid: (Severe) Levodopa is contraindicated for concurrent use with non-selective MAOIs, such as isocarboxazid. Levodopa, a catecholamine precursor, can lead to a relative catecholamine (e.g., dopamine, norepinephrine, and epinephrine) excess when combined with a MAOI. Hypertensive crisis and other adverse cardiovascular effects can occur. At least 2 weeks should elapse between discontinuation of one agent and initiation of therapy with the other.
    Isoflurane: (Major) If administered before halogenated anesthetics, levodopa without a concurrent decarboxylase inhibitor has been associated with cardiac arrhythmias. This interaction is presumably due to the levodopa-induced increases in plasma dopamine. Levodopa single-agent therapy should be discontinued 6 to 8 hours before administering halogenated anesthetics. Otherwise, when general anesthesia is required, levodopa may be continued as long as the patient is permitted to take oral medication. Patients should be observed for signs of neuroleptic malignant syndrome while therapy is interrupted, and the usual levodopa regimen should be administered as soon as the patient is able to take oral medication.
    Isoniazid, INH: (Major) Concurrent use of levodopa with drugs that have MAOI-type activity, such as isoniazid, INH should be avoided if possible. Levodopa, a catecholamine precursor, can lead to a relative catecholamine (e.g., dopamine, norepinephrine, and epinephrine) excess when combined with a MAOI. Hypertension and other adverse cardiovascular effects can occur.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Concurrent use of levodopa with drugs that have MAOI-type activity, such as isoniazid, INH should be avoided if possible. Levodopa, a catecholamine precursor, can lead to a relative catecholamine (e.g., dopamine, norepinephrine, and epinephrine) excess when combined with a MAOI. Hypertension and other adverse cardiovascular effects can occur.
    Isoniazid, INH; Rifampin: (Major) Concurrent use of levodopa with drugs that have MAOI-type activity, such as isoniazid, INH should be avoided if possible. Levodopa, a catecholamine precursor, can lead to a relative catecholamine (e.g., dopamine, norepinephrine, and epinephrine) excess when combined with a MAOI. Hypertension and other adverse cardiovascular effects can occur.
    Isoproterenol: (Major) Levodopa is the metabolic precursor to dopamine. Since a portion of administered levodopa is converted to dopamine peripherally, concomitant administration with isoproterenol should be used with caution as the risk of cardiovascular toxicity is increased.
    Kava Kava, Piper methysticum: (Major) Kava kava, Piper methysticum has been reported to increase the symptoms of Parkinson's disease. The antagonism of dopamine by kava kava could account for the observed effects. Until more is known, concurrent use of kava kava in patients on therapy for Parkinson's disease, like levodopa, should be done only under the care of a health care professional, and use together is not recommended. Monitor the patient for decreased effectiveness of prescribed medications.
    Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with levodopa should generally be avoided because of the possibility of additive sedative effects. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
    Linezolid: (Major) Concomitant use of levodopa (including carbidopa; levodopa and carbidopa; levodopa; entacapone) and drugs with monoamine oxidase inhibitor (MAOI) activity, such as linezolid, can result in hypertensive crisis. Simultaneous use of these agents should be avoided if possible.
    Lisdexamfetamine: (Major) Levodopa, due to its conversion to dopamine, may increase the risk of developing amphetamine-induced cardiac arrhythmias; dosage reductions of lisdexamfetamine may be advisable when the two agents are used concurrently.
    Loop diuretics: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Loxapine: (Major) Loxapine, a dopamine receptor antagonist, is a pharmacologic antagonist to drugs such as levodopa, which is a dopamine agonist. Loxapine can antagonize the actions of this drug.
    Macimorelin: (Major) Avoid use of macimorelin with drugs that may transiently elevate growth hormone concentrations, such as levodopa. Healthcare providers are advised to discontinue levodopa therapy and observe a sufficient washout period before administering macimorelin. Use of these medications together may impact the accuracy of the macimorelin growth hormone test.
    Maprotiline: (Moderate) Maprotiline exhibits antimuscarinic activity and can decrease gastric motility, decreasing the bioavailability of levodopa. In addition, severe hypertension occurred in a limited number of patients who received levodopa in combination with a tricyclic antidepressant.
    Meperidine; Promethazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Mesoridazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Methamphetamine: (Major) Levodopa, due to its conversion to dopamine, may increase the risk of developing amphetamine-induced cardiac arrhythmias; dosage reductions of amphetamines are recommended if the two agents are used concurrently.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Minor) Through its central antimuscarinic actions, hyoscyamine can potentiate the dopaminergic effects of levodopa. Clinicians should be ready to decrease doses of levodopa if hyoscyamine is added.
    Methscopolamine: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
    Methyldopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Methylphenidate: (Moderate) Increased dopaminergic effects may occur during coadministration of methylphenidate, an inhibitor of dopamine reuptake, and medications that increase dopaminergic activity such as levodopa. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible.
    Metoclopramide: (Major) Metoclopramide is a central dopamine antagonist. Metoclopramide can antagonize the actions of dopamine agonists such as levodopa. In addition, metoclopramide may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. Dyskinesias and other extrapyramidal effects have been reported during treatment with various anti-parkinson's medications, particularly levodopa. A symptom complex resembling neuroleptic malignant syndrome in association with rapid dose reduction, withdrawal of, or changes in anti-parkinsonian therapy has also been observed. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and dopamine agonists; however, coadministration should be avoided if possible.
    Metyrosine: (Major) The extrapyramidal effects of metyrosine can antagonize the effects of levodopa. Dosage adjustments of either of these medications may be required.
    Molindone: (Major) In general, antipsychotics can worsen the motor symptoms of Parkinson's disease thereby decreasing the overall effectiveness of antiparkinsonian agents. Molindone should be avoided in patients receiving medications for Parkinson's disease unless the benefit of molindone therapy outweighs the risk of decreased therapeutic response to levodopa or other treatments.
    Oxybutynin: (Minor) Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. Antimuscarinics, by slowing GI transit, may also decrease levodopa bioavailability; however, this mechanism appears to be of modest clinical significance. Antimuscarinic agents targeted specifically for urinary incontinence may be less likely to produce pronounced effects on levodopa response than those with more pronounced systemic action.
    Papaverine: (Major) The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by coadministration of papaverine; avoid concurrent use in these patients. Papaverine may block dopamine receptors in the striatum and result in loss of control of Parkinson's disease in patients who are taking levodopa.
    Perphenazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Perphenazine; Amitriptyline: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Phenelzine: (Severe) Levodopa is contraindicated for concurrent use with non-selective MAOIs, such as phenelzine. due to increased risk of hypertensive crisis. At least 2 weeks should elapse between discontinuation of one agent and initiation of therapy with the other.
    Phenothiazines: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Phenoxybenzamine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Phentolamine: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Phenylephrine; Promethazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Phenytoin: (Moderate) Phenytoin or fosphenytoin can possibly interfere with the effects of levodopa; the mechanism of the interaction has not been established. The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin. Monitor carefully for loss of therapeutic response.
    Pimozide: (Major) Antipsychotic agents may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and should be avoided during therapy for Parkinson's disease unless the benefit of the drug outweighs the risk of decreased therapeutic response to levodopa or other treatments.
    Polysaccharide-Iron Complex: (Major) Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa. Administration of iron salts, including polysaccharide-iron complex, should be separated from levodopa by at least 2 hours.
    Potassium-sparing diuretics: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Pramipexole: (Minor) Pramipexole increases the Cmax of levodopa and decreases Tmax from 2.5 to 0.5 hrs.
    Prazosin: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Procarbazine: (Major) Concomitant use of levodopa and drugs with monoamine oxidase inhibitor (MAOI) activity (e.g., procarbazine) can result in hypertensive crisis. Simultaneous use of these agents should be avoided if possible.
    Prochlorperazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Promethazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Propantheline: (Moderate) Anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
    Propofol: (Major) If administered before halogenated anesthetics, levodopa without concomitant use of a decarboxylase inhibitor has been associated with cardiac arrhythmias. This interaction is presumably due to the levodopa-induced increases in plasma dopamine. Levodopa single-agent therapy should be discontinued 6 to 8 hours before administering halogenated anesthetics. Otherwise, when general anesthetics are required, levodopa may be continued as long as the patient is permitted to take oral medication. Patients should be observed for signs of neuroleptic malignant syndrome while therapy is interrupted, and the usual levodopa regimen should be administered as soon as the patient is able to take oral medication.
    Pyridoxine, Vitamin B6: (Severe) Pyridoxine, vitamin B6, in doses as low as 10 mg/day, can accelerate the rate of aromatic amino acid decarboxylation, thus increasing the peripheral conversion of levodopa to dopamine. This action diminishes levodopa's therapeutic effects by decreasing the amount of levodopa that is available to cross into the CNS. Patients receiving levodopa single-agent therapy should avoid vitamin B6 supplements.
    Rasagiline: (Moderate) There may be some increase in rasagiline blood levels in the presence of levodopa, the effect is modest and rasagiline dosing need not be modified in the presence of carbidopa; levodopa. Rasagiline and carbidopa; levodopa are frequently used together; however, there is the possibility of increased dyskinesia and postural hypotension when combined.
    Reserpine: (Severe) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects. Rauwolfia alkaloids, such as reserpine, deplete dopamine stores in the brain, thereby antagonizing the effects of levodopa.
    Rotigotine: (Moderate) In clinical studies, concurrent use of L-dopa/carbidopa with rotigotine had no effect on the pharmacokinetics of either agent. However, rotigotine may potentiate the dopaminergic side effects of levodopa via a pharmacodynamic interaction. Subsequent worsening of pre-existing dyskinesias may occur.
    S-adenosyl-L-methionine, SAM-e: (Major) Levodopa therapy has been reported to cause a decrease in S-adenosyl-L-methionine, SAM-e, concentrations within the CNS. The implications of this pharmacologic activity are not known at this time. Intracerebral injections of SAM-e have been reported to induce Parkinson's like symptoms in animals. However, at least one clinical report of the use of SAM-e for the treatment of depression in Parkinson's patients has been published. The authors reported that while significant improvement in the Hamilton rating scale for depression occurred, none of the 21 patients required alterations in their levodopa dosage. The motor component of the disease was not affected. Until more is known about the CNS effects of SAM-e supplementation, SAM-e should be used cautiously in patients on levodopa therapy.
    Safinamide: (Moderate) Safinamide and carbidopa; levodopa are indicated for use in combination; however, there is the possibility of new onset dyskinesias or exacerbation of pre-existing dyskinesias. Patients should be advised to contact their health care provider if they notice new or worsening dyskinesias while taking these medicines together.
    Sapropterin: (Major) Coadministration of sapropterin and levodopa has been associated with seizures. Post-marketing safety surveillance showed 3 patients (all with underlying neurologic disorder) develop convulsions, exacerbation of convulsions, over-stimulation, or irritability while receiving concomitant levodopa and sapropterin.
    Scopolamine: (Minor) The doses of antimuscarinics and levodopa may need to be adjusted when the drugs are given simultaneously. Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. While some patients may benefit from this interaction, clinicians should be ready to decrease doses of levodopa if an antimuscarinic is added.
    Selegiline: (Moderate) Concurrent therapy with MAO-B inhibitors and levodopa may be associated with severe orthostatic hypotension not attributable to levodopa alone. Dosages of levodopa should be reduced 2 to 3 days after beginning selegiline therapy.
    Sevoflurane: (Major) If administered before halogenated anesthetics, levodopa without a concurrent decarboxylase inhibitor has been associated with cardiac arrhythmias. This interaction is presumably due to the levodopa-induced increases in plasma dopamine. Levodopa single-agent therapy should be discontinued 6 to 8 hours before administering halogenated anesthetics. Otherwise, when general anesthesia is required, levodopa may be continued as long as the patient is permitted to take oral medication. Patients should be observed for signs of neuroleptic malignant syndrome while therapy is interrupted, and the usual levodopa regimen should be administered as soon as the patient is able to take oral medication.
    Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Major) Iron salts may reduce the bioavailability of levodopa and carbidopa; levodopa. Administration of iron salts, including polysaccharide-iron complex, should be separated from levodopa by at least 2 hours.
    Solifenacin: (Minor) Through central antimuscarinic actions, anticholinergics can potentiate the dopaminergic effects of levodopa. Antimuscarinics, by slowing GI transit, may also decrease levodopa bioavailability; however, this mechanism appears to be of modest clinical significance. Antimuscarinic agents targeted specifically for urinary incontinence may be less likely to produce pronounced effects on levodopa response than those with more pronounced systemic action.
    Solriamfetol: (Moderate) Monitor for dopamine-mediated effects including nausea, vomiting, dizziness, tremor, and changes in moods or behaviors if solriamfetol, a central dopamine and norepinephrine reuptake inhibitor, is administered with other dopaminergic drugs, such as levodopa. Caution is recommended since this combination has not been evaluated.
    Tedizolid: (Major) Concomitant use of levodopa and drugs with monoamine oxidase inhibitor (MAOI) activity (e.g., tedizolid) can result in hypertensive crisis or unstable blood pressure changes. Simultaneous use of these agents should be avoided if possible.
    Tetrabenazine: (Severe) Coadministration of carbidopa; levodopa with tetrabenazine is not recommended. Tetrabenazine can deplete dopamine stores in the brain, thereby antagonizing the effects of levodopa.
    Thiazide diuretics: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Thiethylperazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Thioridazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Thiothixene: (Major) Concomitant use of thiothixene and levodopa is not recommeneded. By blocking dopamine receptors in the brain, thiothixene may inhibit the clinical antiparkinsonian response to levodopa. In addition, concomitant use may cause additive drowsiness. In general, avoid thiothixene in patients requiring therapy for Parkinson's disease unless the benefit of the neuroleptic outweighs the risk of decreased therapeutic response to antiparkinsonian therapy.
    Tranylcypromine: (Severe) Levodopa is contraindicated for concurrent use with non-selective MAOIs, such as tranylcypromine, due to the increased risk of hypertensive crisis. At least 2 weeks should elapse between discontinuation of one agent and initiation of therapy with the other.
    Treprostinil: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
    Tricyclic antidepressants: (Moderate) Tricyclic antidepressants exhibit antimuscarinic activity and can decrease gastric motility, decreasing the bioavailability of levodopa. In addition, severe hypertension occurred in a limited number of patients who received levodopa in combination with a tricyclic antidepressant.
    Trifluoperazine: (Major) Phenothiazines may inhibit the clinical antiparkinsonian response to levodopa by blocking dopamine receptors in the brain and levodopa may decrease the response to phenothiazines by increasing central dopamine levels. In general, phenothiazines should be avoided in patients requiring therapy for Parkinson's disease unless the benefit of the antipsychotic outweighs the risk of decreased therapeutic response to levodopa or phenothiazines.
    Trihexyphenidyl: (Minor) The doses of trihexyphenidyl and levodopa may need to be adjusted when the drugs are given simultaneously. Trihexyphenidyl can potentiate the dopaminergic effects of levodopa.
    Vasodilators: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.

    PREGNANCY AND LACTATION

    Pregnancy

    Levodopa should be used in pregnancy only if the potential benefit outweighs the potential risk to the fetus. There are no adequate or well-controlled studies regarding the developmental risks to the fetus from levodopa use during human pregnancy. Levodopa/carbidopa therapy has been shown to be developmentally toxic in animal studies. Levodopa crosses the placenta in humans and reaches levels in the fetus comparable to maternal blood, although pregnancy outcomes have been primarily unremarkable. Two miscarriages were reported in the first trimester during use of carbidopa/levodopa, and one infant exposed to levodopa in utero was reported to have osteomalacia. One case of neonatal seizure occurred after use of bromocriptine plus carbidopa/levodopa/entacapone during pregnancy. A separate case describes a patient who became pregnant on 2 separate occasions while receiving levodopa and cabergoline for Parkinson's disease. The medications were continued throughout the pregnancies. There were no fetal complications; however, C-section was required in the second birth due to placental abruption. Maternal complications reported in three pregnancies during use of levodopa in combination with carbidopa included first trimester vaginal bleeding, third trimester nausea and vomiting, depression, and preeclampsia. The effects of levodopa in labor and delivery are unknown.

    Excretion of levodopa into breast milk has been reported, and caution is advisable in breast-feeding mothers.[48681] [63854] Because levodopa can inhibit prolactin secretion, interference with proper lactation is possible; however, there are limited data about this potential in lactating women.[48681] [63854] Partial to complete suppression of lactation has been observed in female patients given levodopa for galactorrhea.[48683] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.[48681] [63854] In one case report of a breast-feeding mother with Parkinson's disease receiving sustained-release carbidopa/levodopa 50/200 mg 4 times daily, peak levels of levodopa in milk occurred 3 hours after a dose and returned to baseline after 6 hours. After receiving the same dose of the immediate-release (IR) formulation, similar results were observed, with the exception of higher milk: plasma ratios with the IR product (0.32 vs. 0.28). The infant ingested 0.127 mg and 0.181 mg of levodopa after maternal intake of the sustained-release and immediate-release products, respectively. It was estimated that the infant received an average of 0.3% of the maternal weight-adjusted dosage of the sustained release product and 0.5% of the maternal weight-adjusted dose of the immediate-release product. No adverse effects were observed in her infant, whose development was normal at 2 years of age.[48662] If levodopa must be administered during breast-feeding, the infant should be monitored for commonly encountered adverse effects associated with dopaminergic therapy including dyskinesias, insomnia, sedation, nausea, and constipation.

    MECHANISM OF ACTION

    Mechanism of Action: Levodopa is the metabolic precursor of dopamine. In patients with idopathic Parkinson's disease or parkinsonism, there is a degerneration of the dopaminergic neurons of the substantia nigra, pars compacta and, to a lesser extent, in the ventral temenal area that is associated with a reduction in striatal dopamine content. The severity of the motor deficit is proportional to the dopamine defficiency. Unlike dopamine, levodopa is able to diffuse into the central nervous system, and is then converted to dopamine. The resulting change in dopamine-acetylcholine balance is believed to improve nerve impulse control and to be the basis of the drug's antiparkinsonian activity. Levodopa treatment does not reverse the course or stop the progression of the disease.Patients who experience response fluctations (i.e., dyskinesias, "on-off" effects, etc.) appear to have reduced metabolism of levodopa and storage of dopamine. In these patients, levodopa is metabolized in the extracellular space and dopamine is released directly to the active site. Therefore, the decline in motor function follows the decreases in levodopa concentrations since there is no dopamine storage serving as a buffer. Parkinson's disease patients who do not have response fluctations, exhibit a residual capacity of production and storage of endogenous dopamine and lower doses of levodopa are required. This storage buffer is responsible for the lag time between decline in levodopa concentrations and dopamine-induced motor response. It is not known if response fluctations are also induced by receptor desensitization or inhibition of the active transport of levodopa across the blood-brain barrier by the metabolite of levodopa, 3-O-methyldopa.

    PHARMACOKINETICS

    Levodopa is administered orally and by oral inhalation. When levodopa is administered orally, it is rapidly decarboxylated in extracerebral tissues to dopamine, leaving only a small portion of a dose to be transported unchanged into the central nervous system. The plasma half-life of oral levodopa is about 50 minutes. When levodopa is administered with carbidopa, the half-life is increased to 1.5 hours. The half-life of levodopa following a single orally inhaled dose (84 mg) is 2.3 hours. The two major metabolic pathways are decarboxylation by dopa decarboxylase and O-methylation by catechol-O-methyltransferase (COMT). Levodopa is excreted in the urine primarily as metabolites, including dopamine and homovanillic acid (HVA). Carbidopa reduces the amount of levodopa required for a given response by about 75% and decreases plasma and urinary dopamine and HVA.
     
    Affected Cytochrome P450 isoenzymes and drug transporters: None

    Oral Route

    Following oral administration, amino acid transport mechanisms carry levodopa across the membrane of the gastrointestinal tract. Levodopa competes with certain amino acids for transport across the gut wall; therefore, the absorption of levodopa may be impaired in those on a high protein diet. Any food (i.e., high fat or high protein) or drug that delays gastric emptying may decrease the absorption of levodopa. Iron salts or multivitamins containing iron salts can form chelates with levodopa and reduce the bioavailability of levodopa.

    Inhalation Route

    Following oral inhalation of one 84-mg dose of levodopa, the median time to maximum plasma concentrations of levodopa is about 0.5 hours (range: 0.17 to 2 hours). In fasting healthy volunteers, the bioavailability of levodopa is about 70% relative to immediate-release oral levodopa tablets. The dose-normalized maximum concentration from orally inhaled levodopa is about 50% of that following immediate-release oral tablets.