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			{{Short description|Anti Parkinson medicine}}
	{{Drugbox		{{Drugbox
	| verifiedrevid = 408380698		| verifiedrevid = 448181424
	| image = Stalevo.jpg		| image = Stalevo.jpg
Line 6:		Line 7:
	| type = combo		| type = combo
	| component1 = Carbidopa		| component1 = Carbidopa
	| class1 = ]		| class1 = ]
	| component2 = Levodopa		| component2 = Levodopa
	| class2 = ] ]		| class2 = ] ]
	| component3 = Entacapone		| component3 = Entacapone
	| class3 = ]		| class3 = ]
	<!--Clinical data-->		<!--Clinical data-->
	| tradename =		| tradename = Stalevo, Corbilta, Carlevent
	| Drugs.com = {{drugs.com|CDI|stalevo}}		| Drugs.com = {{drugs.com|ppa|levodopa-carbidopa-and-entacapone}}
	| MedlinePlus = a601068		| MedlinePlus = a601068
	| pregnancy_US = C		| DailyMedID = Stalevo
			| pregnancy_AU = B3
			| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Carbidopa / entacapone / levodopa Use During Pregnancy | website=Drugs.com | date=14 October 2019 | url=https://www.drugs.com/pregnancy/carbidopa-entacapone-levodopa.html | access-date=19 May 2020 | archive-date=28 November 2020 | archive-url=https://web.archive.org/web/20201128133805/https://www.drugs.com/pregnancy/carbidopa-entacapone-levodopa.html | url-status=live }}</ref>
			| pregnancy_category =
			| routes_of_administration = ]
			| ATC_prefix = N04
			| ATC_suffix = BA03
			<!-- Legal status -->
			| legal_AU = S4
			| legal_AU_comment = <ref>{{cite web | title=Stalevo 75/18.75/200 levodopa/carbidopa (as monohydrate)/entacapone tablet bottle (160686) | website=Therapeutic Goods Administration (TGA) | date=27 May 2022 | url=https://www.tga.gov.au/resources/artg/160686| access-date=30 April 2023}}</ref><ref>{{cite web | title=Carlevent levodopa/carbidopa/entacapone 100/25/200 mg tablet bottle (195747) | website=Therapeutic Goods Administration (TGA) | date=26 May 2022 | url=https://www.tga.gov.au/resources/artg/195747 | access-date=1 May 2023}}</ref>
			| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
			| legal_BR_comment =
			| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
			| legal_CA_comment =
			| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
			| legal_DE_comment =
			| legal_NZ = <!-- Class A, B, C -->
			| legal_NZ_comment =
			| legal_UK = POM
			| legal_UK_comment = <ref>{{cite web | title=Stalevo 100 mg/25 mg/200 mg Film-coated Tablets - Summary of Product Characteristics (SmPC) | website=(emc) | date=9 September 2019 | url=https://www.medicines.org.uk/emc/product/6518/smpc | access-date=19 May 2020 | archive-date=2 December 2021 | archive-url=https://web.archive.org/web/20211202164740/https://www.medicines.org.uk/emc/product/6518/smpc | url-status=live }}</ref>
	| legal_US = Rx-only		| legal_US = Rx-only
			| legal_US_comment = <ref name="Stalevo FDA label" />
	| routes_of_administration = Oral
			| legal_EU = Rx-only
			| legal_EU_comment = <ref name="Stalevo EPAR" /><ref>{{cite web | title=Corbilta | website=] (EMA) | date=16 January 2023 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/corbilta | access-date=1 May 2023 | archive-date=3 February 2023 | archive-url=https://web.archive.org/web/20230203113812/https://www.ema.europa.eu/en/medicines/human/EPAR/corbilta | url-status=live }}</ref>
			| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
			| legal_UN_comment =
			| legal_status = Rx-only
	<!--Identifiers-->		<!--Identifiers-->
			| CAS_number = 745835-09-0
	| ATC_prefix = N04
	| ATC_suffix = BA03
	| PubChem = 10550026		| PubChem = 10550026
			| KEGG = D10293
	| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
			| ChemSpiderID = none
	<!--Chemical data-->		<!--Chemical data-->
	}}		}}
	'''Stalevo''' is an ] ] combination medication that contains ], ], and ] for the treatment of ]. It is marketed by Swiss-based ] Pharmaceuticals and manufactured by Finnish drugmaker ].
			'''Carbidopa/levodopa/entacapone''', sold under the brand name '''Stalevo''' among others, is a ] ] that contains ], ], and ] for the treatment of ].<ref name="Stalevo FDA label">{{cite web | title=Stalevo- carbidopa, levodopa, and entacapone tablet, film coated | website=DailyMed | date=30 July 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=53c488d8-4146-7563-8021-d90c931d1a95 | access-date=1 May 2023 | archive-date=6 December 2021 | archive-url=https://web.archive.org/web/20211206095857/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=53c488d8-4146-7563-8021-d90c931d1a95 | url-status=live }}</ref>
	==Indications==
	Stalevo was approved by the FDA in June 2003 to treat adult patients with idiopathic Parkinson’s disease in two scenarios. First, to substitute with equivalent strength of each of the three components for immediate-release carbidopa/levodopa and entacapone previously administered as individual products. Second, to replace immediate-release carbidopa/levodopa therapy (without entacapone) when patients experience the signs and symptoms of end-of-dose "wearing-off" but only for patients taking a total daily dose of levodopa of 600&nbsp;mg or less and not experiencing ]s.<ref name="ntref"> Retrieved 2010-4-1</ref>
	===Extension===		==Medical uses==
			Carbidopa/levodopa/entacapone is indicated for the treatment of ].<ref name="Stalevo FDA label" />
	{{As of|2010}} Applications for extending the indication of Stalevo to patients requiring initiation of levodopa therapy have been under review by the European Medicines Agency (EMEA) and the U.S. Food and Drug Administration (FDA), based on the favourable results from FIRST-STEP, a study conducted in North America and Europe by Novartis from 2005 to 2007 (see below).<ref name="orionstride"> Retrieved 2010-3-31</ref>
			In the European Union it is ] for the treatment of adults with Parkinson's disease and end-of-dose motor fluctuations not stabilized on levodopa/dopa decarboxylase (DDC) inhibitor treatment.<ref name="Stalevo EPAR">{{cite web | title=Stalevo EPAR | website=] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/stalevo | access-date=25 May 2020 | archive-date=31 October 2020 | archive-url=https://web.archive.org/web/20201031022927/https://www.ema.europa.eu/en/medicines/human/EPAR/stalevo | url-status=live }}</ref>
	==Dosing forms==
	Stalevo is supplied as tablets in six strengths<ref name="novinsert"> Retrieved 2010-4-1</ref>:
			==Side effects==
	{| class="wikitable" style="text-align:left;
			Sometimes a wearing off effect may occur at the end of the dosing interval, where a patient may feel Parkinson's symptoms. Urine, saliva, or sweat may be discolored (dark color such as red, brown, or black) after taking carbidopa/levodopa/entacapone.<ref name="drugscom" />
	|+Stalevo Dosing Forums
	|-
	! !! Carbidopa !! Levodopa !! Entacapone
	|-
	! Stalevo 50
	| 12.5 || 50 || 200
	|-
	! Stalevo 75
	| 18.75 || 75 || 200
	|-
	! Stalevo 100
	| 25 || 100 || 200
	|-
	! Stalevo 125
	| 31.25 || 125 || 200
	|-
	! Stalevo 150
	| 37.5 || 150 || 200
	|-
	! Stalevo 200
	| 50 || 200 || 200
	|-
	|}
			==Drug interactions==
	==Dosing==
			Carbidopa/levodopa/entacapone is contraindicated in patients taking a class of ] known as ] such as ] and ].<ref name="epocrates">{{cite web | title=Stalevo: Dosing, contraindications, side effects, and pill pictures | website=Epocrates Online | url=https://online.epocrates.com/noFrame/showPage.do?method=drugs&MonographId=3518&ActiveSectionId=4 | access-date=30 April 2023 | archive-date=5 February 2022 | archive-url=https://web.archive.org/web/20220205031541/https://online.epocrates.com/noFrame/showPage.do?method=drugs&MonographId=3518&ActiveSectionId=4 | url-status=live }}</ref>
	===Adult dosing===
	====Parkinson's disease, idiopathic====
	Maximum 1 tablet per dose, 8 tablets per day (all but the highest strength tablets), 6 tablets per day (Stalevo 200). Tablets are not to be cut, crushed, or chewed.<ref> Retrieved 2010-4-2</ref>
			Carbidopa/levodopa/entacapone may be combined with the drugs ] or ]. These drugs are a different type of MAO inhibitor known as ] that are often prescribed for Parkinson's disease.<ref name="drugscom">{{cite web | title=Carbidopa, entacapone, and levodopa Advanced Patient Information | website=Drugs.com | date=9 December 2022 | url=https://www.drugs.com/cons/carbidopa-entacapone-and-levodopa.html | access-date=1 May 2023 | archive-date=5 July 2022 | archive-url=https://web.archive.org/web/20220705134423/https://www.drugs.com/cons/carbidopa-entacapone-and-levodopa.html | url-status=live }}</ref> Many drug interactions involving selegiline are theoretical, primarily based on interactions with non-selective MAO inhibitors; at oral doses the risk of these interactions may be very low. However, transdermal selegiline, known by its trade name ], is still contraindicated.<ref name="epocrates" /> Transdermal selegiline results in higher plasma levels at which it behaves like a non-selective MAO inhibitor. Concominant use of entacapone, a component of carbidopa/levodopa/entacapone, with MAO inhibitors may increase toxicity of MAO inhibitors. Levodopa, also a component of carbidopa/levodopa/entacapone, in combination with MAO inhibitors may result in ].<ref>{{cite book | vauthors = Leikin JB, Paloucek FP | date = 2007 | url = https://books.google.com/books?id=0Bw2UJTC_uMC&pg=PP1 | title = Poisoning and toxicology handbook | edition = 4th | publisher = Informa Health Care | page = 610 | isbn = 978-1-4200-4479-9 | access-date = 2020-12-06 | archive-date = 2023-05-01 | archive-url = https://web.archive.org/web/20230501030554/https://books.google.com/books?id=0Bw2UJTC_uMC&pg=PP1 | url-status = live }}</ref>
	====Renal dosing====
	Not defined. In severe impairment caution is advised.
	====Hepatic dosing====
	Not defined. In severe impairment caution is advised.
	===Pediatric dosing===
	Pediatric dosing is currently unavailable and/or not applicable.<ref> Retrieved 2010-4-2</ref>
	==Mechanism of action==		==Mechanism of action==
	{{Main|Levodopa|Carbidopa|Entacapone}}		{{Main|Levodopa|Carbidopa|Entacapone}}
	Levodopa is the immediate precursor to dopamine. Entacapone is a selective, reversible ] that increases the bioavailability of levodopa. Entacapone does not cross the blood-brain barrier. Carbidopa is a peripheral ] (AADC) inhibitor. Carbidopa, which also does not cross the blood-brain barrier, is combined with levodopa to prevent its conversion to dopamine in the periphery.<ref name="ntref" />		Levodopa is the immediate precursor to dopamine. Entacapone is a selective, reversible ] that prevents the degradation of levodopa. Entacapone does not cross the blood–brain barrier. Carbidopa is a peripheral ] (AADC) inhibitor. Carbidopa, which also does not cross the blood–brain barrier, is combined with levodopa to prevent its conversion to dopamine in the periphery.<ref name="ntref">{{cite web | title=Drug Reference for FDA Approved Parkinson's Disease Drugs | website=Redirecting | url=http://www.neurotransmitter.net/parkinsons_drug_reference.html | access-date=1 May 2023 | archive-date=7 December 2022 | archive-url=https://web.archive.org/web/20221207133304/https://www.neurotransmitter.net/parkinsons_drug_reference.html | url-status=live }}</ref>{{Unreliable medical source|date=May 2023}}
	==Side effects==
	It is important to take Stalevo at regular intervals according to the schedule outlined by a doctor. Sometimes a weaning off effect may occur at the end of the dosing interval, where a patient may feel Parkinson's symptoms. Urine, saliva, or sweat may be discolored (dark color such as red, brown, or black) after taking Stalevo.<ref name="drugscom" />
	==Drug interactions==
	Stalevo is contraindicated in patients taking a class of ] known as ] such as ] and ].<ref name="epocrates"> Retrieved 2010-4-2</ref> Combining Stalevo with these drugs could cause serious—possibly life-threatening—side effects. MAO inhibitors should be stopped at least two weeks before starting therapy with Stalevo.
	Stalevo may be combined with the drugs ] or ]. These drugs are a different type of MAO inhibitor known as ] that are often prescribed for Parkinson's disease.<ref name="drugscom"> Retrieved 2010-4-2</ref> Many drug interactions involving selegiline are theoretical, primarily based on interactions with non-selective MAO inhibitors; at oral doses the risk of these interactions may be very low. However, transdermal selegiline, known by its trade name ], is still contraindicated.<ref name="epocrates" /> Transdermal selegiline results in higher plasma levels at which it behaves like a non-selective MAO inhibitor. Concominant use of entacapone, a component of Stalevo, with MAO inhibitors may increase toxicity of MAO inhibitors. Levodopa, also a component of Stalevo, in combination with MAO inhibitors may result in ].<ref>Leikin, Jerrold B. & Paloucek, Frank P. (2007). ''''. Informa Health Care. p. 610. ISBN 1-4200-4479-6. Google Book Search. Retrieved on April 2, 2010.</ref>
	==Studies==
	The supporting literature provided with Stalevo notes several studies undertaken to determine the various properties and clinical effectiveness of carbidopa, levodopa, and entacapone in non-combination form.<ref name="novinsert" /> Two studies, STRIDE-PD and FIRST-STEP, have been undertaken specifically to evaluate Stalevo.
	===STRIDE-PD===
	STRIDE-PD (Stalevo Reduction in Dyskinesia Evaluation), is the first long-term clinical trial evaluating Stalevo in Parkinson's disease. It sought to demonstrate a delay in the onset of motor complications such as dyskinesias in patients taking Stalevo compared to those taking a traditional levodopa/carbidopa medication. The study is an international, multi-center, randomized, double-blind, parallel group, active-controlled study. The study was conducted between September 2004 and November 2008 in 77 centers and 14 countries, including 31 sites in the United States, Canada and the following European countries: Austria, Belgium, France, Finland, Germany, Greece, Italy, Spain, Sweden, Turkey, Switzerland, United Kingdom.<ref> Retrieved 2010-3-31</ref> A total of 745 patients enrolled in the trial and 541 completed treatment. Of the patients who completed treatment, 265 patients received Stalevo and 276 received carbidopa/levodopa. Treatment lasted between 2.6 years and 4 years (mean duration: 2.7 years). The average age of patients in the trial was approximately 60 years. The majority of subjects were Caucasian (95.2%) and male (62.7%). The study was aimed to provide support for extending the current EU indication to early Parkinson's disease.
	In February 2009, the result of the primary endpoint measured in STRIDE-PD demonstrated that Stalevo does not delay the onset of involuntary movements, dyskinesia. Therefore the primary objective of STRIDE-PD study was not achieved.<ref name="orionstride" />
	====Prostate cancer data====
	A total of 467 men received randomized treatment in the trial. Among those who received treatment, there was a higher number of cases of ] in patients in the Stalevo group compared those in the carbidopa/levodopa group. Specifically, 9 out of 245 males (3.7%, 95% Confidence Interval: 1.69% - 6.86%) had prostate cancer in the Stalevo group compared to the 2 out of 222 males (0.9%) in the carbidopa/levodopa group. The incidence rate of prostate cancer was 14 cases/1,000 patient years for Stalevo and 3.2 cases/1,000 patient years for carbidopa/levodopa. The odds ratio for the occurrence of prostate cancer in males taking Stalevo was 4.19 (95% Confidence Interval: 0.90– 19.63). Duration of therapy prior to diagnosis of prostate cancer in the Stalevo-treated group ranged from 148 days to 949 days (mean: 664 days).
	Previous clinical trials with Stalevo did not find an increased risk for prostate cancer. Most of these trials evaluating this drug were conducted for less than a year, whereas STRIDE-PD was conducted over a 4 year period, with a mean duration of exposure of 2.7 years.<ref> Retrieved 2010-4-2</ref>
	===FIRST-STEP===
	The FIRST-STEP ('''F'''avorability of '''I'''mmediate-'''R'''elease carbidopa/levodopa vs '''ST'''alevo; '''S'''hort-'''T'''erm comparison in '''E'''arly '''P'''arkinson's) study was a double-blind, randomized, parallel group, fixed-dose, clinical trial that included 423 patients with early Parkinson's disease in eight countries. It was sponsored by Novartis and conducted in the USA, Canada and six other countries between 2005 and 2007. The patients were randomized to receive three daily doses of either Stalevo or levodopa/carbidopa, each containing 100&nbsp;mg of the active drug, levodopa. Each patient received treatment for 9 months. The primary end-point of the study was the change from baseline in combined UPDRS (Unified Parkinson's Disease Rating Scale) part II and III scores measuring activities of daily living and motor function in patients with PD. The treatment difference was statistically significant (p<0.05) in favour of Stalevo. The conclusion was that Stalevo provides better symptomatic benefit than standard levodopa/carbidopa treatment in early Parkinson's Disease.<ref> Retrieved 31-3-2010</ref><ref> Retrieved 31-3-2010</ref>
			==Society and culture==
	==Safety==
	===Prostate cancer===		=== Legal status ===
			Carbidopa/levodopa/entacapone was approved by the US Food and Drug Administration (FDA) in June 2003.<ref>{{cite web | title=Drug Approval Package: talevo 50, 100 & 150 (carbidopa/ levodopa/ entacapone) NDA #021485 | website=U.S. ] (FDA) | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-485_Stalevo.cfm | access-date=1 May 2023 | archive-date=7 April 2021 | archive-url=https://web.archive.org/web/20210407091242/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-485_Stalevo.cfm | url-status=live }}</ref><ref>{{cite web | title=Carbidopa, entacapone, and levodopa Uses, Side Effects & Warnings | website=Drugs.com | date=4 October 2022 | url=https://www.drugs.com/mtm/carbidopa-entacapone-and-levodopa.html | access-date=1 May 2023 | archive-date=13 January 2023 | archive-url=https://web.archive.org/web/20230113160358/https://www.drugs.com/mtm/carbidopa-entacapone-and-levodopa.html | url-status=live }}</ref>
	On March 31, 2010, the United States Food and Drug Administration stated it is evaluating long-term clinical data from STRIDE-PD which found that a greater number of patients taking Stalevo had ] compared to those taking carbidopa/levodopa.<ref> Retrieved 2010-3-31</ref> Other controlled clinical trials evaluating Stalevo or ] (entacapone) did not find an increased risk of prostate cancer. FDA is still reviewing the available information and has not concluded that Stalevo increases the risk of developing prostate cancer. Healthcare professionals were advised to be aware of this possible risk and follow current guidelines for ]. FDA recommended that healthcare professionals follow the recommendations in the drug label when prescribing Stalevo and Comtan. Patients were directed to not stop taking their medication unless directed to do so by their healthcare professional.<ref> Retrieved on 2010-4-2</ref>
	===Cardiovascular risks===
	On August 20, 2010, the United States Food and Drug Administration stated meta-analysis of several studies "appeared to show an increase in the risk of heart attack, stroke, and cardiovascular death for people taking the drug" but also stated "findings were not clear."<ref> Retrieved 2010-8-20</ref> Heart problems are not uncommon in Parkinson's patients and the FDA will investigate the concerns.
	==See also==		== Research ==
			It may help decrease a change of response to Parkinson's medications.<ref>{{cite journal | vauthors = Salat D, Tolosa E | title = Levodopa in the treatment of Parkinson's disease: current status and new developments | journal = Journal of Parkinson's Disease | volume = 3 | issue = 3 | pages = 255–269 | date = January 2013 | pmid = 23948989 | doi = 10.3233/JPD-130186 | doi-access = free }}</ref>
	* ]
	* ]
	* ]
	==References==		== References ==
	{{Reflist}}		{{Reflist}}
	==External links==		== External links ==
			* {{cite web | title=Entacapone/Carbidopa/Levodopa (marketed as Stalevo) Information | publisher=U.S. ] (FDA) | date=6 April 2017 | url=http://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/entacaponecarbidopalevodopa-marketed-stalevo-information }}
	*{{official|http://www.stalevo.com}}
	{{Antiparkinson}}		{{Antiparkinson}}
			{{Dopamine receptor modulators}}
			{{Monoamine metabolism modulators}}
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			{{DEFAULTSORT:Carbidopa Levodopa Entacapone}}
	]		]
	]		]