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The product is available in 6 strengths, each in a 1:4 ratio of carbidopa to levodopa and bined with entacapone 200 mg. Generally, the product should be used to substitute for patients already stabilized on equivalent doses of carbidopa/levodopa and entacapone. However, some patients stabilized on a given dose of carbidopa/levodopa may be treated with this product if a decision to add entacapone has been made. The optimum daily dosage must be determined by careful titration in each patient. Therapy should be individualized and adjusted according to the desired therapeutic response. Transferring Patients to Carbidopa/Levodopa/Entacapone PO There is no experience in transferring patients currently treated with standard formulations of carbidopa/levodopa other than immediate-release carbidopa/levodopa with a 1:4 ratio and entacapone to carbidopa/levodopa/entacapone. Patients who are taking entacapone 200 mg with each dose of standard-release carbidopa/levodopa can be directly switched to the corresponding strength of Stalevo containing the same amounts of levodopa and carbidopa. Transferring Patients Not Currently Taking Entacapone PO Patients should be titrated individually with a carbidopa/levodopa product (ratio 1:4) and an entacapone product. Then, once the patient has stabilized, transfer patient to a corresponding dose of carbidopa/levodopa/entacapone.

Since entacapone prolongs and enhances the effects of levodopa, therapy should be individualized and adjusted, if necessary, according to the desired therapeutic response. General Advice Administer prescribed dose without regard to meals. Administer with food if GI upset occurs however, do not administer with high-protein foods because they reduce absorption of medication. Administer only 1 tablet at each dosing interval. If an increased dose is needed, a different tablet strength will need to be administered.

The max remended dose of Stalevo. defined by the max daily dose of entacapone, is 8 tablets daily, which would include a total of entacapone 1,600 mg. Individualize and adjust therapy for each patient according to the desired therapeutic response. When less levodopa is required, the total daily dose of carbidopa/levodopa should be reduced either by decreasing the carbidopa/levodopa/entacapone strength or by decreasing the frequency of administration. When more levodopa is required, the next higher strength of carbidopa/levodopa/entacapone should be taken and/or the frequency of doses should be increased, up to a max of 8 times daily of Stalevo . Standard drugs for Parkinson disease may be coadministered with carbidopa/levodopa/entacapone however, dosage adjustments may be required.

Storage/Stability Store at controlled room temperature (59deg to 86degF). Drug Interactions Antihypertensive agents Symptomatic postural hypotension may occur when adding carbidopa/levodopa therefore, be prepared to adjust antihypertensive therapy as needed. Dopamine D2 receptor antagonists (eg, butyrophenones, isoniazid, phenothiazines, risperidone), papaverine, phenytoin May reduce the therapeutic effects of levodopa. Drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidase (eg, ampicillin, chloramphenicol, cholestyramine, erythromycin, probenecid, rifampin) Because entacapone is excreted via the bile, use drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidase with caution. Drugs metabolized by T (eg, alpha-methyldopa, apomorphine, bitolterol, dobutamine, dopamine, epinephrine, isoproterenol, isotharine) Increased heart rate, possible arrhythmia, and excessive BP changes may occur.

Iron salts May reduce the bioavailability of levodopa however, the clinical importance is unclear. Concurrent therapy with nonselective MAOIs (eg, phenelzine) is contraindicated. Discontinue therapy with MAOIs 2 wk prior to starting carbidopa/levodopa/entacapone. Metoclopramide May increase levodopa bioavailability by increasing gastric emptying and because of its dopamine receptor antagonistic properties metoclopramide may also adversely affect disease control. Pyridoxine Pyridoxine in doses of 10 to 25 mg may reverse the effects of levodopa however, carbidopa inhibits this effect of levodopa. Therefore, supplemental pyridoxine can be given concurrently. Tricyclic antidepressants (TCAs) (eg, amitriptyline) Rare reports of adverse reactions, including hypertension and dyskinesia, have been noted with conitant use of levodopa/carbidopa and TCAs. Laboratory Test Interactions False-positive reactions for urinary ketone bodies may occur when a test tape is used for ketonuria determination false-positive Coombs test results may occur because falsely diagnosed pheochromocytoma has occurred, exercise caution when interpreting plasma and urine levels of catecholamines and their metabolites.

Adverse Reactions Cardiovascular Carbidopa/Levodopa Cardiac irregularities, hypertension, hypotension, orthostatic hypotension, palpitation, phlebitis, syncope. Carbidopa/Levodopa Abnormal dreams (including nightmares), agitation, asthenia, bradykinetic episodes (ldquoon-offrdquo phenomenon), confusion, convulsions, dementia, depression with and without suicidal tendencies, dizziness, dyskinesia, hallucinations, headache, increased libido, insomnia, NMS, paranoid ideation, paresthesia, psychotic episodes (including delusions), somnolence. Entacapone Dyskinesia (25) hyperkinesia (10) hypokinesia (9) dizziness (8) fatigue (6) anxiety, asthenia, somnolence (2) agitation (1). Abnormal gait, activation of latent Horner syndrome, anxiety, ataxia, blepharospasm, decreased mental acuity, disorientation, euphoria, extrapyramidal disorder, falling, fatigue, increased tremor, malaise, memory impairment, muscle twitching, nervousness, numbness, peripheral neuropathy, sense of stimulation, trismus. What Is Carbidopa/Entacapone/Levodopa Levodopa is converted to a chemical called dopamine (DOE pa meen) in the brain. Symptoms of Parkinson39s disease may be caused by low levels of dopamine in the brain. Carbidopa helps prevent the breakdown of levodopa before it can reach the brain and take effect. Entacapone increases levels of levodopa in the body. The bination of carbidopa, entacapone, and levodopa is used to treat Parkinson symptoms such as muscle stiffness, tremors, spasms, and poor muscle control.

Carbidopa, entacapone, and levodopa may also be used for purposes not listed in this medication guide. You should not use this medication if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate) in the last 14 days. You should not take this medication if you are allergic to carbidopa (Lodosyn), entacapone (tan), or levodopa (Larodopa), or if you have narrow-angle glaua, unusual skin lesions, or a history of skin cancer. Tell your doctor about all of your medical conditions, especially heart disease, high blood pressure, asthma or other breathing problems, liver or kidney disease, a hormonal disease, an ulcer, glaua, or mental illness. Also tell your doctor about all the medications you use. It may take up to several weeks of using carbidopa, entacapone, and levodopa before your symptoms improve. Talk with your doctor if your symptoms do not improve or if the effects of this medication seem to wear off quickly in between doses.

Do not stop using carbidopa, entacapone, and levodopa without first talking to your doctor. Do not take this medication if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate) in the last 14 days. You should not take this medication if you are allergic to carbidopa (Lodosyn), entacapone (tan), or levodopa (Larodopa), or if you have: narrow-angle glaua unusual skin lesions that have not been checked by a doctor or a history of malignant melanoma (skin cancer). To make sure you can safely take this medication, tell your doctor if you have any of these other conditions: heart disease, high blood pressure, coronary artery disease, a heart rhythm disorder, or a prior heart attack asthma, chronic obstructive pulmonary disease (COPD), or other breathing disorder kidney disease, liver disease, or bile duct obstruction an endocrine (hormonal) disease a stomach or intestinal ulcer glaua or depression or other mental illness.

You may have increased sexual urges, unusual urges to gamble, or other intense urges while taking this medication. Talk with your doctor if you believe you have any intense or unusual urges while taking this medicine. Carbidopa, entacapone, and levodopa may cause hallucinations (the sensation of hearing or seeing something that is not there). Call your doctor if you experience hallucinations.

Some people taking Parkinson39s disease medications have developed skin cancer (melanoma). However, people with Parkinson39s disease may have a higher risk of melanoma. Talk to your doctor about this risk and what skin symptoms to watch for. You may need to have regular skin exams. FDA pregnancy category C. It is not known whether carbidopa, entacapone, and levodopa will harm an unborn baby. Tell your doctor if you are pregnant or plan to bee pregnant while using this medication. Carbidopa, entacapone, and levodopa may pass into breast milk and could harm a nursing baby. You should not breast-feed while you are taking carbidopa, entacapone, and levodopa. Carbidopa/Entacapone/Levodopa Side Effects Get emergency medical help if you have any of these signs of an allergic reaction: hives difficulty breathing swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as: nausea, sweating, feeling like you might pass out (especially when you first start taking this medication) depression, confusion, hallucinations, unusual thoughts or behavior, thoughts about hurting yourself worsening symptoms such as tremors, twitching or uncontrollable movements of your eyes, lips, tongue, face, arms, or legs severe or ongoing diarrhea, extreme thirst, increased urination, weight loss, leg disfort, muscle weakness or limp feeling, uneven heart rate feeling very thirsty or hot, being unable to urinate, heavy sweating, or hot and dry skin fast, pounding, or uneven heartbeats chest pain or heavy feeling, pain spreading to the arm or shoulder, general ill feeling tight feeling in your chest, new or worsening cough, fever, trouble breathing easy bruising or bleeding, bloody or tarry stools, coughing up blood pain or burning when you urinate or unexplained muscle pain, tenderness, or weakness. Less serious side effects may include: stomach pain or upset, loss of appetite, constipation dry mouth, changes in your sense of taste unusual skin changes. mild rash or itching dizziness or drowsiness, headache, blurred vision muscle cramps, back pain or agitation or anxiety, sleep problems (insomnia), strange dreams. You may notice that your sweat, urine, or saliva appears dark in color, such as red, brown, or black. This is not a harmful side effect, but it may cause staining of your clothes or bed sheets.

This is not a plete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Carbidopa/Entacapone/Levodopa Interactions Carbidopa, entacapone, and levodopa may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall. Avoid taking iron supplements or eating a diet that is high in protein (protein sources include meat, eggs, and cheese). These things can make it harder for your body to digest and absorb carbidopa, entacapone, and levodopa. Cold or allergy medicine, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression or anxiety can add to sleepiness caused by carbidopa, entacapone, and levodopa. Tell your doctor if you regularly use any of these other medicines, or any other Parkinson39s medications.

Tell your doctor about all other medicines you use, especially: apomorphine (Apokyn) cholestyramine (Prevalite, Questran) dobutamine (Dobutrex) epinephrine (Epi-Pen, and others) isoniazid (for treating tuberculosis) isoproterenol (Isuprel, Medihaler-Iso) methyldopa (Aldomet) metoclopramide (Reglan) papaverine (Pavabid, Papacon, Pavagen, Pavacot) phenytoin (Dilantin) probenecid (Benemid) blood pressure medication an antibiotic such as ampicillin, chloramphenicol, erythromycin (E. E.S. EryPed, Ery-Tab, Erythrocin, Pediazole, and others), or rifampin (Rifadin, Rifater, Rifamate) an antidepressant such as amitriptyline (Elavil, Vanatrip, Limbitrol), doxepin (Sinequan), imipramine (Janimine, Tofranil), nortriptyline (Pamelor), and others or medicines to treat psychiatric disorders, such as chlorpromazine (Thorazine), haloperidol (Haldol), prochlorperazine (pazine), risperidone (Risperdal), and others. This list is not plete and other drugs may interact with carbidopa, entacapone, and levodopa. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Carbidopa/Entacapone/Levodopa Dosage Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than remended.

Follow the directions on your prescription label. Take your medicine at regular intervals to keep a steady amount of the drug in your body at all times. Drink plenty of liquids while you are taking this medication. It may take up to several weeks before your symptoms improve. Keep using the medication as directed and tell your doctor if your symptoms do not improve after a few weeks of treatment. Also tell your doctor if the effects of this medication seem to wear off quickly in between doses. Call your doctor if you have ongoing vomiting or diarrhea, or if you are sweating more than usual. You can easily bee dehydrated while taking this medication, which can lead to severely low blood pressure or a serious electrolyte imbalance. Do not stop using carbidopa, entacapone, and levodopa without first talking to your doctor.

You may need to use less and less before you stop the medication pletely. This medication can cause unusual results with certain medical tests. Tell any doctor who treats you that you are using carbidopa, entacapone, and levodopa. Store at room temperature away from moisture and heat. Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Overdose symptoms may include weakness, loss of coordination, trouble breathing, fainting, or seizure (convulsions). Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Copyright 1996-2016 Cerner Multum, Inc. Latest Update: 3/18/2015, Version: 4.01About DailyMed DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts). This Web site provides a standard, prehensive, up-to-date, look-up and download resource of medication content and labeling found in medication package inserts. The National Library of Medicine (NLM) provides this as a public service and does not accept advertisements. The drug labeling information on this Web site is the most recent submitted to the Food and Drug Administration (FDA) and currently in use it may include, for example, strengthened warnings undergoing FDA review or minor editorial changes. These labels have been reformatted to make them easier to read. Introduction: Parkinsonx02019s disease (PD) is a mon neurodegenerative disease. In the 1960s, it was shown that the degeneration of dopamine producing neurons in the substantia nigra (SN) caused the motor features of PD. Dopamine replacement with levodopa, a dopamine precursor, resulted in remarkable benefit. Yet, the intermittent administration of levodopa is a major cause of motor plications, such as x0201cwearing-offx0201d of levodopax02019s benefit and involuntary movements, known as dyskinesia.

Therefore, agents that prolong levodopax02019s half-life were employed, such as carbidopa, an aromatic amino acid decarboxylase (AADC) inhibitor, and entacapone, a catechol-O-methyltransferase (T) inhibitor. The bination product carbidopa/levodopa/entacapone (CLE) was approved in 2003 for the treatment of PD patients. To assess the evidence for the place of CLE in the treatment of PD. Evidence review: Place in therapy: Abbreviations: PDQ-39, Parkinsonx02019s Disease Questionnaire-39 (quality of life assessment tool) PDQ-8: Parkinsonx02019s Disease Questionnaire-8 (quality of life) UPDRS, Unified Parkinsonx02019s Disease Rating Scale (part II scores activities of daily leaving and part III objective motor performance) CGI-C, Clinical Global Impression of Change QOL-VAS: Quality Of Life-Visual Analog Scale CL: carbidopa/levodopa CLE, carbidopa/levodopa/entacapone. Scope, aims, and objectives The bination product of levodopa, carbidopa and entacapone is known generically as x0201ccarbidopa/levodopa/entacaponex0201d, but will be referred to here as CLE. Levodopa, an aromatic amino acid, is the most efficacious treatment of Parkinsonx02019s disease (PD) that was developed in the late 1960s.1 It is the precursor of dopamine and crosses the blood-brain barrier, unlike dopamine. However, only 1 of an oral levodopa dose reaches the brain.

Approximately 70 of oral levodopa is metabolized by aromatic amino acid decarboxylase (AADC) in the intestinal mucosa and liver. That leads to increased dopamine levels in the periphery resulting in side effects, namely postural hypotension, nausea and vomiting.2 Carbidopa is an inhibitor of peripheral AADC. Its addition to levodopa since the 1970s has decreased the incidence of the aforementioned side effects and increased the availability of levodopa to the brain. It increases the half-life of levodopa from 60 to 90 minutes, thus allowing for a 90 levodopa dose reduction to achieve the same benefit.3 Carbidopa is used in the USA and benserazide or carbidopa in Europe.

However, this strategy shifts the peripheral metabolism of levodopa to another pathway. Catechol-O-methyltransferase (T) transfers the methyl group of S-adenosyl-L-methionine to levodopa producing 3-O-methyldopa (3-OMD), an inactive pound at the periphery, and 3-methoxytyramine (3-MT) in the brain.2 ,4 Entacapone is a peripheral T inhibitor. Its pharmacokinetics are unaltered by conitant administration of levodopa/AADC inhibitor, age, gender, race or multiple dosing (no accumulation has been observed with up to 10 times daily dosing).4 Its time to peak concentration (t max ) is 2 hours with a half-life of 0.4 to 0.9 hours, both similar to levodopa. It inhibits by 65 the T activity in human erythrocytes after a dose of 200 mg. Its bioavailability is between 29 and 46 and is albumin bound by 98. When given together with a dose of levodopa/carbidopa, it increases both levodopax02019s half-life and its area under the curve (AUC) by up to 85 and 50, respectively. At the same time, it does not affect the peak concentration (C max ) and t max of levodopa.4 x020136 Finally, it does not interact with pounds that are metabolized by T, such as epinephrine, isoproterenol, alpha-methyldopa, dopamine, dobutamide, AADC inhibitors and nadolol, or increase the (nor)epinephrine plasma levels when used conitantly with imipramine or monoamine oxidase (MAO) A inhibitors.4 The clinical efficacy of entacapone was observed in prospective, randomized, double-blind studies on PD patients with motor fluctuations (levodopa positive effect x0201cwears-offx0201d typically before the next dose). Ruottinen and Rinne observed that the addition of 200 mg of entacapone to each dose of levodopa/carbidopa increased the x0201conx0201d time (when patient experiences benefit from levodopa) by 2.5 hours and reduced by 16 the daily levodopa dose.6 In the SEESAW study, entacapone increased daily x0201conx0201d time by 1 hour, decreased the daily levodopa dose by 12 and improved activities of daily living (ADL), motor and total scores of the Unified Parkinsonx02019s Disease Rating Scale (UPDRS).7 In the NOMET study, the daily x0201conx0201d time increased by 1.4 hours with levodopa daily dose reduction of 12.8 This effect was sustained in a 3-year open label extension of the study. In the CELOMEN study, the daily x0201conx0201d time increased by 1.7 hours, the daily x0201coffx0201d time decreased by 1.5 hours, the mean daily levodopa dose was reduced by 54 mg, and the ADL, motor and total UPDRS scores improved.9 In the UK-IRISH study, the daily x0201conx0201d time increased by 1.3 hours and the x0201coffx0201d time decreased by 1.1 hours.10 These results coupled with bioequivalence studies lead to CLE approval by the US Food and Drug Administration (FDA) in 2003 for substitution of carbidopa/levodopa (CL) and entacapone taken separately and for replacing CL in PD patients experiencing x0201cwearing-offx0201d signs and symptoms (for patients taking daily levodopa dose up to 600 mg and not experiencing dyskinesia). The aim of this article is to review the evidence for safety, tolerability, efficacy and cost-effectiveness of CLE and its place in the treatment of PD. We reviewed the literature by using the PubMed, Medline and Cochrane databases. We used the search terms x0201cStalevox0201d and x0201centacaponex0201d.

The search produced 21 articles about CLE in PubMed and Medline bined and zero articles in Cochrane database. Of these, 8 articles were foreign, could not be obtained, and were excluded. Of the remaining, 9 articles were original papers, 3 were review articles and 1 was an abstract about cost-effectiveness. We included unpublished, to this point, data from the STRIDE-PD study. Disease overview Parkinsonx02019s disease is named after James Parkinson who published in 1817 a monograph with the title x0201cAn Essay on the Shaking Palsyx0201d.11 The incidence of PD is about 14 per 100,000 population per year overall but increases to 160 for the population aged 70 years or older. The median prevalence is 9.4 per 1000 with a 2 risk for developing PD by the age of 80. It affects approximately 1 million individuals in the USA.12 ,13 The mortality rate was reported to be 3-fold greater in PD patients before the introduction of levodopa. This was reduced to 1.6-fold in the post-levodopa era with a trend to increase again.14 ,15 The pathologic hallmark of PD is the loss of dopamine producing neurons in the substantia nigra (SN) acpanied by the intraneuronal accumulation of alpha-synuclein containing Lewy bodies (LB) resulting in dopamine deficiency.16 ,17 There is much research on the etiology and pathogenesis of PD. Although genetic causes account for only 10 of the cases, the discovery of gene products and their function gave us better insight as to the possible pathogenic mechanisms.

In particular, the concept of protein mishandling seems important, and involves the ubiq-uitin-proteasomal system and the lysosomes. Mitochondrial dysfunction, oxidative stress, apoptosis, and inflammation are also important mechanisms that possibly interact with each other.18 x0201322 Environmental factors can have a harmful (like pesticides),23 or protective effect (cigarette smoking).24 PD typically has an asymmetric onset with bradykinesia, rest tremor, rigidity and postural instability being its cardinal motor features.22 ,25 Bradykinesia is the most characteristic manifestation of PD and presents with slowness of movements resulting in loss of facial expression (hypomimia), low volume soft voice, reduced blinking, drooling and slow gait with poor arm swing. It is due to dopamine deficiency and failure of the positive feedback from the basal ganglia to the frontal cortex.26 Rest tremor is a 4 to 6 Hz oscillatory movement involving the distal parts of the extremities, such as hand (x0201cpill-rollingx0201d tremor) and foot. It is unilateral at onset and more prominent on the side it started when the disease progressively involves the other side. Interestingly, some patients report postural tremor years before the onset of PD.27 Rigidity is the resistance during passive movement of the limb, neck, or trunk. It may be associated with pain. Painful shoulder is a mon initial manifestation of PD and usually misdiagnosed as of musculoskeletal origin.28 Postural instability is the loss of postural reflexes and usually occurs in later stages. It is demonstrated when a patient loses his balance while pulled forward or backward by the shoulders (x0201cpull testx0201d).26 In addition to the cardinal features, there are other motor manifestations of PD. Freezing is a sudden and transient loss of movement for a few seconds and typically involves the gait. It is a frequent cause of falls and can be only partially relieved by levodopa therapy.

Other features are dysarthria, dysphagia, sialorrhea, decreased ocular convergence, and appearance of primitive reflexes, such as glabellar and pal-momental.26 Nonmotor manifestations of PD are thought to be derived from neurotransmitter deficits other than dopamine, as opposed to most of the classic motor features.29 ,30 Those are categorized into neuropsychiatric, sleep, autonomic, and sensory symptoms. Neuropsychiatric manifestations include depression, anxiety, apathy, psychosis, and cognitive impairment. Dysautonomia can manifest as orthostatic hypotension, hyperhidrosis, erectile dysfunction, constipation and bladder dysfunction. Finally, sensory symptoms take the form of olfactory dysfunction, akathisia, paresthesia, and pain.26 ,29 ,30 Current therapy options Treatment for PD falls into three categories: therapies, medications and surgery. We will focus on the treatment of the cardinal motor features of PD, the majority of which are dopamine responsive. Physical and other therapies, surgery and the treatment of the nonmotor nondopamine responsive symptoms are beyond the scope of this article the reader is referred to detailed reviews of these topics.22 ,31 ,32 The cardinal motor features of PD, bradykinesia and rigidity, respond very well to dopamine replacement treatment. Tremor can be less responsive, whereas postural instability shows the least response to dopaminergic strategies.

Levodopa is the most effective medication and has been employed in the treatment of PD since the late 1960s.1 ,33 Currently, we have a variety of dopaminergic and non-dopaminergic medications available. Dopaminergic agents are: dopamine precursor (levodopa), decarboxylase inhibitors (carbidopa, benserazide), dopamine agonists (pramipexole, ropinirole, pergolide, bromocriptine, apomorphine, cabergoline, lisuride), T inhibitors (entacapone, tolcapone), type B MAO inhibitors (selegiline, rasagiline) and dopamine releaser/anti-glutamergic (amantadine). Anti-cholinergics have been used since the 1950s for symptomatic relief, due to their anti-muscarinic effect. However, they result in memory impairment and hallucinations, especially in the elderly. Therefore, they are rarely used. They are less effective than their dopaminergic counterparts.

The most significant benefit is on tremor severity.22 ,31 ,32 Over time, treatment with levodopa is associated with x0201cwearing-offx0201d phenomenon (treatment effect wears off with return of parkinsonian symptoms) and dyskinesia (choreiform involuntary movements and dystonia). The ELLDOPA study showed a dose-response improvement in UPDRS scores, but also a dose-response effect regarding motor plications, with dyskinesia occurring in 16.5 and wearing-off in 28 of patients treated with daily levodopa dose of 600 mg for 9 months.34 On the other hand, the CALM-PD study pared pramipexole to levodopa with respect to their potential for developing motor plications. Pramipexole-treated patients had less incidence of dyskinesia (10 versus 31) and wearing-off periods (24 versus 38) after 2 years.35 Pramipexole was less effective and associated with more somnolence than levodopa. Therefore, in early PD patients there is some debate about whether to initiate treatment with levodopa or dopamine agonists. In the treatment of moderate and more advanced disease non-levodopa medications are not effective and the introduction of levodopa is required.22 ,31 ,32 Unmet needs The major unmet need is the discovery of a neuroprotective treatment.

To date, there is no definite evidence for any of the marketed medications to be neuroprotective. A detailed discussion is beyond the scope of this article and the reader is referred to relevant reviews.22 ,31 The management of motor plications (wearing-off and dyskinesia) poses significant problems in clinical practice. The pathogenesis of the motor plications is believed to be derived from the pharmacokinetics of the dopaminergic medications (especially levodopa) and the reduced dopamine-producing neurons in the substantia nigra (SN). Normally, the SN delivers dopamine to the striatum in a tonic, continuous manner. In PD patients we substitute the deficit in dopamine production with an intermittent pattern of delivery, owing to the short half-life of levodopa and the decreased buffering potential of the remaining functioning SN neurons.

This nonphysiologic pattern results in postsynaptic alterations that involve gene transcription and the firing pattern of the basal ganglia output neurons. Therefore, the current trend is to develop strategies that provide continuous dopaminergic stimulation.31 Clinical evidence with carbidopa/levodopa/entacapone In the first section we discussed the evidence for the use of entacapone. Entacapone has a similar pharmacokinetic profile to levodopa, and taken together increases levodopax02019s half-life and bioavailability. This approach leads to increasing the daily x0201conx0201d time, decreasing the daily x0201coffx0201d time and the daily levodopa dose.6 x0201310 A product that bines carbidopa, levodopa, and enta-capone in one tablet should have similar pharmacokinetic and efficacy profile.

However, the initial step is to prove bio-equivalence between CL and entacapone taken separately and bined in one tablet. Four bioequivalence studies tested CLE at different doses (two with CLE containing 50 mg of levodopa, another with 100, and the fourth with 150 mg of levodopa per CLE tablet). There were 40 healthy volunteers per study. They used an open, randomized, crossover and replicate design. They administered either the test drug (CLE) or the reference drug (CL and entacapone) after an overnight fast. Fifteen blood samples were drawn at the same point in time for up to 12 hours after drug administration. Plasma concentrations of levodopa, carbidopa, and entacapone were measured. To determine bioequivalence they calculated the area under the concentration-time curve from 0 up to 12 hours (AUC 1x0201312 h ), C max . t max . and the elimination half-life for levodopa, carbidopa, and entacapone separately. The bioequivalence criteria were met for all three ponents of all different CLE doses, the levodopa half-life for CLE being 1.7 hours (range 1.2 to 3.1 hours).36 Efficacy, safety, and tolerability All the CLE studies that assessed efficacy, safety and tolerability will be analyzed.

The endpoints for efficacy were the UPDRS, Parkinsonx02019s Disease Questionnaire-39 (PDQ-39: including quality of life assessment), Parkinsonx02019s Disease Questionnaire-8 (PDQ-8: quality of life), Clinical Global Impression (CGI for patients and investigators), Quality Of Life-Visual Analog Scale (QOL-VAS). Safety was assessed by the rate of adverse event (AE), and tolerability by the discontinuation rate. The first study to assess safety and tolerability of CLE in PD patients was conducted by the SELECT-TC Study Group an open-label, single-arm, 4-week investigation. They recruited PD patients, experiencing wearing-off, with or without mild dyskinesia. All were receiving a stable dose of immediate release formulation CL (25/100) for at least 1 month prior to study entry. Patients were directly switched from immediate release CL to the equivalent dose of CLE. Tolerability was the primary endpoint. The secondary points were percentage with new onset dyskinesia and worsening of pre-existing dyskinesia.

Safety assessments included adverse events and measurement of vital signs, EKG, physical examination, and blood and urine values. One hundred and sixty-nine patients were studied. The mean age was 66 years and mean disease duration was 5.23 years. The mean Hoehn and Yahr (Hx00026Y) stage was 2.28 and 23 had mild dyskinesia at study entry. Eight percent of patients discontinued the study, the majority due to adverse events, including nausea, worsening of x0201coffx0201d periods, blurred vision, headache, vivid dreams, lightheadedness, and joint pain. Dyskinesia developed in 8.5 of subjects without history of dyskinesia and it worsened in 43.6 of those with pre-existing dyskinesia. The majority improved in their dyskinesia with or without reducing the CLE dose. All adverse events were mild and infrequent with nausea being the most frequent (in 12.4 of patents). No clinical relevant changes in vital signs or laboratory testing were noted.37 The conclusion was that the CLE was tolerated by subjects previously treated with immediate release formulation CL (25/100). The TC-INIT study group conducted the first randomized, multinational, parallel-group clinical trial that pared the efficacy and safety of CLE to CL and entacapone in PD patients with end-of-dose wearing-off and a mean levodopa treatment duration of 5 to 6 years.38 They randomized 77 patients to CLE and 88 to CL and entacapone.

They used three different CLE doses: 50/12.5/200 mg, 100/25/200 mg and 150/37.5/200 mg (for levodopa/carbidopa/entacapone respectively). In both groups, the mean age of disease onset was 60 years, the mean disease duration was 6 years, the mean levodopa dose was 472 mg in the CL and entacapone and 493 mg in the CLE group and all patients had mild to moderately advanced disease (Hx00026Y from 1 to 3). They all had wearing-off for at least 1 year and were on a stable dose of CL only, for at least 6 weeks prior to study entry. The study prised a 2-week dose adjustment period, a 6-week treatment period and a 2-week follow up. Adverse events were reported by 55 of the total population without significant difference between treatment groups. 75 of the adverse events were classified by the patients as x0201cmildx0201d, 24 as x0201cmoderatex0201d and 1 as x0201cseverex0201d. Nausea was the most mon with a trend to be more frequent in the CLE group (14 versus 9). Influenza-like symptoms were reported only to CLE group (7), whereas dyskinesia was more mon in the CLE group (7 versus 3). Discontinuation rate was 5 in the CLE and 3 in the CL and entacapone group. Eighty percent of the patients responded that they preferred taking CLE pared with two separate tablets. The mean levodopa dose did not change significantly in either group pared with baseline.

The primary efficacy variables were the CGI scores, UPDRS change in part III (motor performance), and the total levodopa dose at week 6. In respect to CGI score, 73 of the patients in the CLE and 76 in the CL and entacapone group reported improvement. The investigator CGI scores improved in 79 of patients in both groups. UPDRS part III scores significantly improved in both the CLE and CL and entacapone groups ( P x0003c001 and P 0.0016 respectively). The QOL-VAS was significantly better in the CLE group pared with the CL and entacapone group.

The conclusion of this trial was that both groups were effective and well tolerated. Another study assessed the conversion from sustained release CL (SR-CL), or SR-CL and entacapone, or SR-CL and standard CL with or without entacapone to CLE. It was an open-label study with one month follow up. The conversion was done overnight. Each SR-CL 50/200 mg (carbidopa/levodopa, respectively) converted to CLE 37.5/150/200 mg (carbidopa/levodopa/entacapone, respectively) and each SR-CL 25/100 mg to CLE 25/100/200 mg. They recruited 62 PD patients with mean age of 67 years, disease duration of 11 years and daily levodopa dose of 670 mg. 80 of the patients were having wearing-off at baseline and 47 dyskinesia. 13 out of 62 patients (21) withdrew before the end of the 1-month period due to adverse events. They were older than the CLE group who pleted the study (73 versus 66 years) with longer disease duration (12.5 versus 10 years).

Withdrawals were due to nausea in 54, increased x0201coffx0201d time in 38.5, and dyskinesia, dizziness and insomnia in 23. None of these subjects had been previously exposed to entacapone. Forty-nine patients pleted the 1-month follow-up. Forty-two preferred CLE and 7 SR-CL. Adverse events were less frequent in the CLE than the SR-LC group. Twenty-one were taking entacapone at baseline. In these patients, there were significant improvements only in UPDRS motor scores, by 7 points. In the entacapone-nax000efve patients, there were significant improvements in UPDRS motor scores (by 4 points) and PDQ-39 activities of daily living (ADL) score by 6 points. 78.6 of the entacapone-nax000efve patients and 86 of the total study population preferred CLE over SR-CL. Those who preferred SR-CL were older (68.6 versus 65.7 years) and had longer disease duration (11.7 versus 10.0 years).39 The conclusion of this trial was that CLE was preferred by most patients to SR-CL. The Sim Study was a single group, open, crossover, multicenter, phase III study that assessed the switch from CL and entacapone to CLE. Fifty-two PD patients were included. Mean age was 61 years, age at onset of PD was 53 years, disease duration was 9 years, duration of levodopa treatment was 8 years, daily levodopa dose was 509 mg and duration of entacapone treatment was 2 years. It consisted of a 4 week control phase (patients continued their usual regimen), a 4-week treatment phase (patients received CLE at equivalent dose) and a 2-week follow up period (patients returned to their baseline treatment).

Efficacy parameters were patient preference, UPDRS and QOL-VAS scores. 54 of the patients preferred CLE pared with 31 who preferred the previous treatment ( P 0.162). 86 of all the levodopa doses were directly replaceable. UPDRS scores (part I for cognition and mood, part II for ADL and part III for motor performance) improved from a mean of 35.6 at baseline by 2.5 points ( P x0003c 0.01). UPDRS part III scores improved from 24 by 1.9 points ( P x0003c 0.01). The mean daily levodopa dose in the CLE group was lower by 24.6 mg (from 509 mg at baseline). There was no difference in the QOL-VAS score. Three patients (6) discontinued due to adverse events. Seventeen out of 52 patients developed mild to moderated adverse events. Most mon were dyskinesia, nausea, diarrhea, and influenza-like symptoms.40 The conclusion of this study was that some measures were improved on CLE pared with CL. The Spanish Stalevo Study Group assessed whether or not the dose of levodopa should be reduced when switching from CL to CLE in patients with wearing-off and without or with mild dyskinesia at baseline in order to avoid emergence or worsening of dyskinesia. It was a multicenter, prospective, single-blind, randomized and clinically controlled 4 week study.

Thirty nine patients were randomized to either group A (receiving the same dose of levodopa in the form of CLE) or group B (reducing the dose of levodopa contained in CLE by 15 to 25). Efficacy endpoints were UPDRS, PDQ-39, CGI change and home x0201con-offx0201d diaries. Mean age was 68 years in group A and 67 in group B. PD duration was 8.5 and 9.4 years, levodopa duration 7.5 and 8.7 years with a daily dose of 566 mg and 670 mg respectively. Hx00026Y stage was II to III in 75 of the patients, but more patients with stage IV were in group A. UPDRS total score at baseline was 55 in group A and 58 in B. Seven patients in group A and eight in group B had dyskinesia at baseline. Six patients in group A (35) and 5 in group B (22.7) experienced mild and transient adverse events. Nausea, dizziness, somnolence, and abdominal pain were the most mon. One patient in group A discontinued due to increased dyskinesia.

Objective increase of dyskinesia was documented in two patients in each group. Group A patients experienced a significant increase in x0201conx0201d time of 76 minutes and significant decrease on x0201coffx0201d time of 123 minutes. Group B experienced a modest increase in x0201conx0201d time of 38 minutes and decrease in x0201coffx0201d time of 32 minutes. The daily x0201conx0201d with dyskinesia increased by 33 minutes in group A and by 98 minutes in group B. Total UPDRS score improved by 1 point in x0201conx0201d state and 6 points in x0201coffx0201d state in group A, and by 3 and 5 points respectively in Group B. PDQ-39 and CGI results regarding quality of life did not change significantly, but more than 60 of patients felt better in both groups. Dyskinesia was not a major problem in this study. The conclusion of this study was that there was no advantage to reducing the dose of levodopa when switching to CLE.41 The START-M open 6 week trial assessed the efficacy, safety and tolerability of CLE when PD patients with wearing off switched from CL. Fifty patients were included with a mean age of 66.7 years, mean disease duration of 6.8 years and a mean daily levodopa dose of 540 mg. 38 of patients had Hx00026Y stage 2 (bilateral parkinsonism without postural instability), 41 stage 2.5 (bilateral disease and instability with recovery on pull test) and 32 stage 3 (bilateral disease with instability and no recovery on pull test). Twenty-seven percent of the patients had dyskinesia. The daily levodopa dose in the form of CLE was equivalent to the baseline dose.

Assessment tools were the UPDRS score, motor fluctuation questionnaire and CGI scores. By week 6 there was a significant ( P x0003c 0.001) reduction of the total UPDRS score from 46.5 to 36 points (29 reduction). Subscale reductions (mean) were as follows: part I by 1.1 points (30), part II by 3.6 points (25) and part III by 4.8 points (24.7). Mean daily x0201coffx0201d time reduced by 1.7 hours. Improvement rate based on CGI was 52 (patient assessment) and 72 (physician assessment). Fewer than 10 of patients experienced side effects, mainly nausea, orthostatic dizziness and headache.

None of them required intervention.42 This open trial showed improvements on many measures when patients switched to CLE. The QUEST-AP study group addressed the question whether CLE treatment improved quality of life when pared with CL treatment in PD patients without or with minimal, nondisabling motor fluctuations. It was a randomized, double-blind, parallel-group, active-controlled multicenter 12-week trial. Inclusion criteria were PD patients with Hx00026Y stage of 1 to 2.5, with 0 to 3 hours of non-disabling daily x0201coffx0201d time and total daily levodopa dose between 300 mg and 800 mg for at least 1 month prior to study entry. Patients with dyskinesia were excluded. The primary oute was a change in the total PDQ-8 score. PDQ-8 is a motor and non-motor eight domain questionnaire ranging from 0 (no impairment) to 32. It is highly correlated with the PDQ-39 assessment tool. Secondary oute measures were the UPDRS (parts I, II, III and IV) scores and the proportion of patients experiencing wearing off periods.

Seventy percent had no fluctuations at baseline and 30 had non-disabling motor plications (UPDRS part IV score was only 1.3 of a maximum of 23). One hundred and eighty four patients were randomized to either CLE or CL treatment groups in a 1:1 ratio. They found a 1.4 point difference in the PDQ-8 score favoring CLE treatment ( P 0.41). UPDRS part II score improved in CLE group ( P 0.032) and part III score improved in both groups. The percentage of patients reporting at least one wearing off symptom dropped from 78.5 to 62 in the CLE group and from 84.5 to 61.5 in the CL group. The difference between groups was not significant.

Fourteen patients (7.6) discontinued the study, six in CLE and four in the CL groups. At least one adverse event was reported by 66 and 56 of patients in the CLE and CL group respectively. More mon adverse events were urine discoloration, nausea, dizziness, constipation, and diarrhea. Mild dyskinesia was reported in 5 patients in the CLE group (5.4) and 1 patient in the CL group (1.1).43 This study failed to show its primary oute. The FIRST-STEP study group evaluated the safety, tolerability and efficacy of CLE pared with CL in early PD patients warranting levodopa treatment.

It was a 39-week, multicenter, randomized, double-blind, parallel-group study. Eligible patients needed to have UPDRS part II plus part III scores of more than 18 points and Hx00026Y stage 1x020132.5. Patients with more than 5-year disease duration were excluded. Mean age was 65 years, mean disease duration 1.16 years and mean UPDRS (part II and III) score was 34. Only 2.4 of patients were on levodopa, 8 on dopamine agonists, and 34 on other PD medications. They were randomized 1:1 to CLE (25/100/200) mg 3 times daily (tid) or CL (25/100) mg tid. Primary oute was the change in UPDRS (part II and III) scores.

Secondary outes were the change in UPDRS subscale scores, PDQ-39 and PDQ-8 scores, Hx00026Y stage, Schwab and England (S E) ADL score, and CGI scores. Treatment success was defined as a reduction of UPDRS total score of more than 8 points. The mean change in total UPDRS score was 10 points in the CLE and 8.5 points in the CL group favoring CLE ( P 0.045). Secondary efficacy results showed greater improvement with CLE in UPDRS ADL (part II) subscale by 3 points ( P 0.025), SE scores by 5.6 points ( P 0.003) and patient CGI ( P 0.047). No significant change noted in UPDRS part III (motor score), PDQ-39, PDQ-8 and Hx00026Y stage. Interestingly, there was no significant change in the incidence of dyskinesia and off-time between groups. Dyskinesia was observed in 11 (5.3) subjects in the CLE and 16 (7.4) in the CL group. Twenty-four patients (11.6) in the CLE and eighteen (8.4) in the CL group discontinued due to AE. The incidence of AE was higher in the CLE (82) than the CL (60) group. Nausea and diarrhea were the most mon.44 The primary oute was achieved in this trial. The STRIDE-PD study evaluated whether CLE would delay the onset of dyskinesia pared with CL in patients with early PD requiring levodopa treatment.

In this multi-center study, 747 patients were randomized to either CLE 25/100/200 mg or CL 25/100 mg with dosing every 3.5 hours and up to 400 mg of daily levodopa dose. Treatment duration was variable between 134 and 208 weeks. The primary endpoint was the time to onset of dyskinesia. It was reported that patients treated with CLE had shorter time to dyskinesia and higher incidence of dyskinesia.45 Therefore, the study did not achieve its goal. Cost effectiveness In one study conducted in the UK, cost-effectiveness of CLE was pared to standard care in PD patients with wearing-off using the Markov model. The costs and outes of both treatments were projected over a period of 10 years.

Sensitivity analyses were used to assess the confidence level of the results. CLE produced a reduction in the total 10-year direct cost to society of 10,198 per patient. The Monte Carlo sensitivity analysis indicated that the likelihood of CLE being either x0201cdominantx0201d (ie, better clinical oute with lower cost) or more effective at an acceptable cost was 93 even when all uncertainties associated with the model were taken into account. When pared to standard care, the probability that CLE would be cost-effective to the society as a whole was 77.46 We should interpret the results of this study with caution as to its ability to be generalized to other countries. Patient group/population The population in the CLE studies consisted mainly of PD patients with early to moderately advanced disease, with non-disabling wearing-off symptoms and mild, if at all, dyskinesia. This is particularly true for the studies that pared CL to CLE, either on direct switch from the former to the latter,41 ,42 or paring directly the two treatments.43 ,44 The mean disease duration ranged from 1.16 to 9 years. The Hx00026Y stage ranged from 1 (unilateral disease) to 3 (bilateral disease with postural instability). The only study that included more advanced patients was the one that assessed switching from SR-CL to CLE.39 This studyx02019s population were patients with disease duration of more than 10 years, with 80 experiencing wearing-off and 47 dyskinesia at baseline. Those being nax000efve to entacapone had higher AE and discontinuation rates.

Dosage, administration, and formulationcarbidopa-levodopa-entacapone This bination medication is used to treat symptoms of Parkinsons disease (such as shakiness, stiffness, difficulty moving). Parkinsons disease is thought to be caused by too little of a naturally occurring substance (dopamine) in the brain. Levodopa changes into dopamine in the brain. helping to control movement. Carbidopa and entacapone prevent the breakdown of levodopa in the bloodstream so more levodopa can enter the brain. Carbidopa can also reduce some of levodopas side effects such as nausea and vomiting .

How to use carbidopa-levodopa-entacapone Take this medication by mouth with or without food as directed by your doctor, usually 3 to 4 times a day. Take only one tablet for each dose. Swallow the tablet whole. Do not crush, chew, or split the tablet. Doing so may cause you to get the wrong dose and may also cause staining of the mouth. dentures, and saliva. See also Side Effects section. Taking this medication with food may help to decrease nausea. It is best to avoid a high-protein diet (it decreases the amount of levodopa that your body takes in) during treatment, unless directed otherwise by your doctor.

Also avoid taking this medication with a high-fat, high-calorie meal since this can slow down the time it begins to work by about 2 hours. Separate your dose of this medication by as many hours as possible from any iron supplements or products containing iron (such as multivitamins with minerals) you may take. Iron can reduce the amount of this medication absorbed by the body. Consult your doctor or pharmacist for more details. The dosage is based on your medical condition and response to treatment. Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day. Some patients may experience a wearing-off (worsening of symptoms) before the next dose is due. An on-off effect might also occur, in which sudden short periods of stiffness occur. If these effects occur, contact your doctor for possible dose adjustments that may help to lessen this effect.

Do not stop taking this medication without consulting your doctor. Some conditions may bee worse when this drug is suddenly stopped. Your dose may need to be gradually decreased. (See also Side Effects section.) Tell your doctor if your condition does not improve or if it worsens. Side Effects Diarrhea. nausea, vomiting, dizziness. lightheadedness, drowsiness, stomach upset, loss of appetite, trouble sleeping.

headache. or dry mouth may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly. This medication may cause saliva.

urine, or sweat to turn a dark color. This effect is harmless, but your clothes may be stained. To reduce the risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position. Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects. Some people taking this medication have fallen asleep suddenly during their usual daily activities (such as talking on the phone, driving). In some cases, sleep occurred without any feelings of drowsiness beforehand. This sleep effect may occur anytime during treatment with this medication even if you have used this medication for a long time.

If you experience increased sleepiness or fall asleep during the day, do not drive or do other possibly dangerous activities until you have discussed this effect with your doctor. Your risk of this sleep effect is increased by using alcohol or other medications that can make you drowsy. See also Precautions section. Tell your doctor right away if you have any serious side effects, including: new/worsening movements you cant control/spasms, greatly increased eye blinking/twitching. fainting. diarrhea that doesnt stop, vision changes (such as blurred vision ), eye pain. severe stomach/abdominal pain.

black/tarry stools, vomit that looks like coffee grounds, muscle pain /tenderness/weakness. change in the amount of urine, mental/mood changes (such as confusion, hallucinations. thoughts of suicide ), signs of infection (such as sore throat that doesnt go away), easy bleeding/bruising, unusual tiredness, tingling of the hands/feet, unusual strong urges (such as increased gambling, increased sexual urges). Get medical help right away if you have any very serious side effects, including: chest pain . Suddenly stopping or reducing the dose of this medication may rarely cause a very serious condition called neuroleptic malignant syndrome (NMS). Get medical help right away if you have any of the following symptoms: fever, unusual muscle stiffness, severe confusion, sweating.

fast/irregular heartbeat. rapid breathing. A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction. including: rash.

itching /swelling (especially of the face/tongue /throat), severe dizziness, trouble breathing . This is not a plete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist. In the US - Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at fda. gov/medwatch. In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345. Precautions Before taking this medication, tell your doctor or pharmacist if you are allergic to carbidopa, levodopa, or entacapone or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems.

Talk to your pharmacist for more details. Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, glaua, breathing problems (such as asthma), heart disease (such as heart attack, irregular heartbeat), kidney disease. stomach/intestinal ulcer, mental/mood disorders (such as depression, schizophrenia), blood disorders. seizures, sleep disorders. This drug may make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages. See also Side Effects section.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products). During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor. Levodopa passes into breast milk. It is unknown if carbidopa or entacapone pass into breast milk. Consult your doctor before breast-feeding. Interactions See also How to Use section. Drug interactions may change how your medications work or increase your risk for serious side effects.

This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctors approval. Some products that may interact with this drug include: antipsychotic drugs (such as chlorpromazine, haloperidol, thioridazine), certain drugs used to treat high blood pressure (such as methyldopa, reserpine), tetrabenazine. Taking MAO inhibitors with this medication may cause a serious (possibly fatal) drug interaction. Avoid taking MAO inhibitors (isocarboxazid, linezolid, methylene blue, moclobemide, phenelzine, procarbazine, tranylcypromine) during treatment with this medication. Most MAO inhibitors should also not be taken for two weeks before treatment with this medication. However, certain MAO inhibitors (rasagiline, selegiline) may be used with careful monitoring by your doctor. Ask your doctor when to start or stop taking this medication.

Tell your doctor or pharmacist if you are taking other products that cause drowsiness including alcohol, antihistamines (such as cetirizine, diphenhydramine), drugs for sleep or anxiety (such as alprazolam, diazepam, zolpidem), muscle relaxants (such as carisoprodol, cyclobenzaprine), and narcotic pain relievers (such as codeine, hydrocodone). Check the labels on all your medicines (such as allergy or cough-and-cold products) because they may contain ingredients that cause drowsiness. Ask your pharmacist about using those products safely. This medication may interfere with certain laboratory tests (including urine catecholamine/glucose/ketone tests), possibly causing false test results.

Make sure laboratory personnel and all your doctors know you use this drug. If overdose is suspected, contact a poison control center or emergency room right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: severe dizziness, fast/irregular heartbeat, mental/mood changes (such as agitation). Do not share this medication with others. Laboratory and/or medical tests (such as heart/kidney/liver function, plete blood count) should be performed periodically to monitor your progress or check for side effects.

Consult your doctor for more details. People with Parkinsons disease may have an increased risk for developing skin cancer (melanoma). Tell your doctor promptly if you have a mole that gets bigger or looks different, or if you have other unusual skin changes. Ask your doctor if you should have regular skin exams. Missed Dose If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up. Store at room temperature away from light and moisture. Do not store in the bathroom.

Keep all medications away from children and pets. Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal pany. Information last revised December 2015. Copyright(c) 2015 First Databank, Inc. DRUG DESCRIPTION Stalevoreg (carbidopa, levodopa and entacapone) is a bination of carbidopa, levodopa and entacapone for the treatment of Parkinsons disease. Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline pound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (-)-L-(alpha-hydrazino-(alpha-methyl-beta-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is C 10 H 14 N 2 O 4 H 2 O, and its structural formula is Tablet content is expressed in terms of anhydrous carbidopa, which has a molecular weight of 226.3. Levodopa, an aromatic amino acid, is a white, crystalline pound, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (-)-L-alpha-amino-beta-(3,4-dihydroxybenzene) propanoic acid.

Its empirical formula is C 9 H 11 NO 4 . and its structural formula is Entacapone, an inhibitor of catechol-O-methyltransferase (T), is a nitro-catechol-structured pound with a molecular weight of 305.3. The chemical name of entacapone is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N, N-diethyl-2-propenamide. Its empirical formula is C 14 H 15 N 3 O 5 and its structural formula is Stalevoreg (carbidopa, levodopa and entacapone) is supplied as tablets in six strengths: Stalevo (carbidopa, levodopa and entacapone) reg 50, containing 12.5 mg of carbidopa, 50 mg of levodopa and 200 mg of entacapone Stalevo (carbidopa, levodopa and entacapone) reg 75, containing 18.75 mg of carbidopa, 75 mg of levodopa and 200 mg of entacapone Stalevo (carbidopa, levodopa and entacapone) reg 100, containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone Stalevo (carbid

Stroke Health Center

Stroke Health CenterViagra: Good for the Brain, Too This content has not been reviewed within the past year and may not represent WebMDs most up-to-date information. To find the most current information, please enter your topic of interest into our search box. WebMD News Archive Feb. 8, 2002 -- Viagra, the g best known for reviving mens sex lives, may also revitalize the brain. according to new research. An animal study suggests that the anti-impotence g can reduce the effects of stroke by helping the brain heal itself. What we found is that we can use certain gs like Viagra to create new brain cells, said study author Michael Chopp, PhD, scientific director of the Neuroscience Institute at Henry Ford Hospital, in a news release. And these cells are created in both elderly as well as young subjects. Chopp presented his research today at the 27th International Stroke Conference in San Antonio, Texas. He says Viagra was selected for testing in stroke treatment because it is chemically similar to otherpounds that have been shown to improve brain function in animals after stroke . In the study, researchers gave rats Viagra for six days after inducing an ischemic stroke (the mostmon type of stroke caused by a blockage of an artery that supplies blood to the brain).

After 28 days, they found the rats that received the g grew significantly more new brain cells. The Viagra-treated rats also performed better on agility, sensory, and muscle function tests. When animals are treated with Viagra, the g provides very significant. benefit to the brain. These animals do better on many different oue measures, said Chopp. Researchers say additional studies have also shown that Viagra given one day after stroke reduced function problems in animals. However, human clinical trials to test Viagra as a treatment after stroke are still a long way off. Additional testing is needed to determine the best time for treatment and screen for adverse effects in rats.

Medications Your doctor will probably prescribe several medicines after you have had a stroke. Medicines to prevent blood clots are typically used, because blood clots can cause TIAs and strokes. The types of medicines that prevent clotting are: Anticoagulant medicines. Antiplatelet medicines.

Cholesterol - lowering and blood - pressure-lowering medicines are also used to prevent TIAs and strokes. Anticoagulant medicines Anticoagulants such as warfarin (for example, Coumadin ) prevent blood clots from forming and keep existing blood clots from getting bigger. You may need to take this type of medicine after a stroke if you have atrial fibrillation or another condition that makes you more likely to have another stroke. For more information, see the topic Atrial Fibrillation. Stroke Treatment Window Widens This content has not been reviewed within the past year and may not represent WebMDs most up-to-date information.

To find the most current information, please enter your topic of interest into our search box. WebMD News Archive May 28, 2009 -- After a stroke. youve got very little time to get treatment. But some patients now have a bit more time. A stroke occurs when a clot cuts off blood flow to parts of the brain. Those parts of the brain soon start to die. A g called tissue plasminogen activator -- tPA -- dissolves clots and restores blood flow. Clearly, the g must be given as soon as possible after a stroke. With every passing minute, more brain cells die. But in the real world, it takes time to get a patient to a hospital. How long does a patient have before the benefits of tPA treatment outweigh its very real risk of causing uncontrollable bleeding in the brain When tPA was first discovered, it was thought that there might be a six-hour window. But U. S. clinical trials suggested that window was only half as wide -- and current rmendations discourage tPA use more than three hours after onset of a stroke.

Last year, European clinical trials found that selected patients still benefit from tPA up to 4 1/2 hours after a stroke . Now, an advisory from the American Heart Association formally spells out which patients might benefit from later tPA treatment. But the chairman of themittee that issued the advisory -- Gregory J. del Zoppo, MD, professor of medicine and adjunct professor of neurology at University of Washington, Seattle -- warns patients not to misinterpret the statement. The message is that stroke patients still need toe in for treatment as soon as possible. There is no benefit in waiting, del Zoppo tells WebMD. Despite the fact that patients whoe in even 3 to 4 1/2 hours after stroke can benefit, they should not wait. There are some patients for whom the smaller benefit of late tPA treatment cannot outweigh the very real risk of hemorrhage. Patients who cannot receive tPA more than three hours after a stroke: Patients over age 80 Patients taking blood thinning gs (anticoagulants) Patients with a history of stroke and diabetes Del Zoppo says researchers still have not learned why strokes progress more slowly in some patients than in others. It would be a major advance, he says, if doctors could identify late-arriving stroke patients who might still benefit from tPA treatment.

Until then, he says, If you really want the best results. youd bettere in straight away after a stroke. The new AHA advisory appears in the August issue of the AHA journal Stroke. Aspirin Taken Right After a Stroke May Prevent a Second One WebMD Health News This content has not been reviewed within the past year and may not represent WebMDs most up-to-date information. To find the most current information, please enter your topic of interest into our search box. WebMD News Archive June 1, 2000 -- Chalk another one up for aspirin. Researchers have concluded that giving aspirin to stroke victims as soon as they arrive at the hospital reduces their risk of having a second stroke . In the first few days after having a stroke.

patients are at high risk of having another one, says Richard Peto, a professor at Oxford University and co-author of an analysis published in the journal Stroke. We found that aspirin didnt do very much for repairing the damage done already by the initial stroke, but. it reduced the likelihood of having another stroke in the hospital, he tells WebMD. Whats more, he says, it appears to be beneficial to give aspirin to stroke victims right away even if doctors arent 100 sure which type of stroke the patient has had. There are two kinds of strokes: ischemic stroke, caused by a clot that blocks a blood vessel supplying the brain with blood. and hemorrhagic or bleeding stroke, caused by a leaky blood vessel that bleeds into the brain. A CT scan of the head can help a doctor determine if a stroke is the ischemic or hemorrhagic type. Aspirin, which thins the blood and thereby prevents clots, is currently used to reduce the long-term risks of a second stroke in patients whove had an ischemic stroke. But giving aspirin to patients whove had a hemorrhagic stroke is considered dangerous, as it can cause more bleeding and more damage. Basically, doctors on the whole tend to wait for things to settle down they wait until theyre sure of the diagnosis -- whether it is ischemic or hemorrhagic, Peto says.

If you start aspirin a bit earlier -- the first week or two is the time of highest risk -- its the time actually when aspirin is most protective. And what we have shown is that you can safely start aspirin early on. Peto and colleagues analyzed the results of two very large studies, involving a total of 40,000 stroke patients, and found thatpared to patients who didnt get aspirin, a third fewer of the patients who received aspirin had a recurrent stroke. Put another way, giving aspirin to 1,000 people prevented about nine deaths or recurrent strokes. Understanding Stroke -- the Basics What Is a Stroke When the blood supply to the brain is intepted or blocked for any reason, the consequences are usually dramatic. Control over movement, perception, speech, or other mental or bodily functions is impaired, and consciousness itself may be lost.

Diptions of blood circulation to the brain may result in a stroke -- a disorder that occurs in two basic forms, both potentially life-threatening. Clots near the brain . About three-quarters of all strokes are due to blockage of the oxygen-rich blood flowing to the brain. Called ischemic strokes, they are triggered by either a thrombus (a stationary clot that forms in a blood vessel) or an embolus (a clot that travels through the bloodstream and bes lodged in a vessel). This type of stroke may be preceded by a brief transient ischemic attack. or TIA -- an episodes of inadequate blood flow that may produce these symptoms: Sudden numbness or weakness on one side of the body An inability to talk Double or blurred vision in one eye Sudden dizziness or falling A TIA usually lasts 15 minutes or less. Because these may be signs of an impending stroke.

take them seriously and see your doctor immediately. With a TIA, circulation and the vital oxygen supply are quickly restored and lasting brain damage is usually avoided. With any stroke, however, if the inteption of blood flow lasts long enough to kill brain cells, it can produce irreversible damage. Bleeding in the brain . The second basic type of stroke is a cerebral hemorrhage, or bleeding in the brain.

It occurs when a brain aneurysmptures or when a weakened or inflamed blood vessel in the brain starts to leak. An aneurysm is a pouch that balloons out from a weakened spot on the wall of an artery. As blood flows into the brain, the buildup of pressure may either kill the tissue directly or destroy cells by impeding normal circulation to the affected region. This typically produces an exciating headache. sometimes followed by loss of consciousness. In contrast to ischemic strokes, which are generally survived, massive bleeding strokes are fatal about 40 of the time within the first month. Is Your Blood Pressure in Check

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Sizetrac Extender Reviews - Does Size Really MatterSizetrac Extender Reviews 8211 Does Size Really Matter Sizetrac Extender Reviews 8211 Does Size Really Matter by Kim Lee 2014-12-11 No man can deny the importance of his penis size when ites to sex. The general consensus is, the bigger the better. No matter how effort, enthusiasm and passion a man exhibits during a sexual intercourse, it will not amount to the impression and impact created by a larger or longer penis. As harsh as it may sound, that is simply the law of nature that every living being on earth lives by. So what goes wrong when you have a penis that is below the average size Well first of all, men with small penises find themselves in a very difficult situation with the ladies. It goes without saying that women are naturally attracted to large penises so any man who doesnt possess one will unfortunately stand second in line. In addition to that, a man with an undersized penis is unlikely to have a sexual experience that is as euphoric as the one enjoyed by those who have relatively larger sized penises. Sexual partners may actually grow bored and strated with men who fail to measure up to their expectations. As a result, the mans sex life bes disappointing and this eventually leads to a great deal of dissatisfaction in the mans life. In short, men with small penis sizes are not only missing out on the women, they are also being deprived of the ecstasy of a thrilling sexual experience. How can this problem be solved Well, you cant really waft a magic wand over your genital and expect it to grow. A man needs to take certain measures to enhance the length or girth of his undersized penis.

There are plenty of herbal male enhancement pills out there in the market but in most cases, they fail to produce reliable results. Sizetrac offers apletely different solution. It is a penis traction device designed to increase the size of your penis. In other words, its a device that stimulates natural penis enlargement. It can also be used to treat Peyronies Disease which or Penile Curvature, a degenerative condition where the penis tends to unnaturally and undesirably curve upwards or downwards. In such cases, sexual intercourse bes painful or impossible. Working Mechanism of Sizetrac The human body adapts and changes under pressure.

Sizetrac makes use of this very biological principal to augment your penis. It applies a constant pressure over the length of your penis and thereby sets off the penis growth process. As mentioned before, its a natural method of penis enlargement and it takes place because of sensitivity and reactive nature of penile tissues. When pressure is applied for long periods of time, the cells in the penile tissue develop and multiply in numbers.

This is similar to how braces on a teeth work. In fact, this principle of traction has been used to increase the size of different parts of the body. For instance, the women of the Paduang tribe in Burma use metal rings to enhance the growth of their necks using a similar method. In the jungles of Africa and Amazonia, men and women apply pressure on their ears and lips to extend it. So as far as the authenticity of this traction method goes, its safe to say that it has been in use for centuries and has produced the desired results. For those suffering from Peyronies disease, wearing the Sizetrac can gradually correct the curvature of the penis. It extends the penis firmly but steadily for a long duration that allows the patient to stretch the limp penis for several hours a day. Sizetrac Extender Reviews The working mechanism of Sizetrac seems quite fail proof. However, it still isnt a clear indicator of whether the product lives up to the level of performances that it promises or promotes. The only way to find that out, is by digging through customer testimonials. Unlike websites other products which are centred around male enhancement, the official website of Sizetrac provides clear andprehensive testimonials in the form of client or customer mails.

Some of the clients were so satisfied with the results that they even posted an entire story about how this device changed their lives for the better. You have in depth stories of how it improved their sex lives, relationships and even marriages. You have people thanking the manufacturers for making their lives interesting again. In fact, I even stumbled upon a note of thanks from the girlfriend of a particular user who was ecstatic about her boyfriends renewed sexual enthusiasm. Above is an example of user review/client mail. How to Buy Sizetrac Online Sizetrac can be bought from the official website which is sizetrac. This is the best place to buy Sizetrac from if youre living in and around the UK. It can also be bought online in Asia. Some websites distributes the product to consumers in Singapore.

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