Product information and disease description Place of product in therapy Approaches to treatment Current treatment options and standard of care

Levodopa

12 evidence topics · 11 sources

Initial therapy: levodopa compared with dopamine agonists in early disease

“Initial treatment with levodopa provides superior motor benefit compared to treatment with dopamine agonists, whereas levodopa is more likely than dopamine agonists to cause dyskinesia.” (opens the source at this quote in a new tab)
“Long-acting forms of levodopa and levodopa with entacapone do not appear to differ in efficacy from immediate-release levodopa for motor symptoms in early disease.” (opens the source at this quote in a new tab)
“There is a higher risk of impulse control disorders associated with the use of dopamine agonists than levodopa.” (opens the source at this quote in a new tab)
“The trend over time demonstrates that levodopa provides greater benefit for motor symptoms than DAs, with the majority of studies demonstrating significantly greater improvement in the participants’ UPDRS part III score for up to 5 years of follow-up.” (opens the source at this quote in a new tab)
“With longer periods of follow-up, an increasing proportion of participants (90% of patients at 6 years and 100% at 10 years) originally randomized to DAs were taking supplemental levodopa, therefore minimizing the difference between groups for this outcome.” (opens the source at this quote in a new tab)
“Initial treatment with levodopa is more likely to induce dyskinesia than initial treatment with DAs for up to 5 years of follow-up, but the prevalence of severe or disabling dyskinesia during this 5-year period is low.” (opens the source at this quote in a new tab)
“The minimal clinically important difference (MCID) in the UPDRS part III score was determined by consensus to be 3 points; changes of 1 point or less were considered unimportant.” (opens the source at this quote in a new tab)
“The MCID in the risk of dyskinesia was determined by consensus to be 15%; RDs ≤5% were considered clinically unimportant.” (opens the source at this quote in a new tab)

Time point	Change in UPDRS part III score, raw mean difference, levodopa minus dopamine agonist (negative values favor levodopa)	Dyskinesia, risk difference, levodopa minus dopamine agonist (positive values indicate higher risk with levodopa)
2 years	“−5.0 [−7.2 to −2.5], moderate confidence”	“18.7% [95% confidence interval (CI) 13.7%–23.8%], moderate confidence”
4 years	“−4.9 [−7.8 to −1.9], low confidence”	“29.2% [19.6%–38.8%], moderate confidence”
5 years	“−3.4 [−5.2 to −1.6], moderate confidence”	“17.5% [4.5%–30.5%], low confidence”

Guideline recommendations for prescribing levodopa in early disease

“Clinicians should initially prescribe IR levodopa rather than CR levodopa or levodopa/carbidopa/entacapone in patients with early PD.” (opens the source at this quote in a new tab)
“In patients with early PD, clinicians should prescribe the lowest effective dose of levodopa (i.e., the lowest dose that provides adequate symptomatic benefit) to minimize the risk of dyskinesia and other adverse effects.” (opens the source at this quote in a new tab)
“Clinical trials in early PD demonstrate symptomatic benefit with levodopa/carbidopa at dosages of 150–300 mg/d and a lower risk of dyskinesia with dosages less than 400 mg/d.” (opens the source at this quote in a new tab)
“IR levodopa is less costly than other levodopa formulations.” (opens the source at this quote in a new tab)

First-line treatment recommendations in the United Kingdom

“Offer levodopa to people in the early stages of Parkinson's disease whose motor symptoms impact on their quality of life.” (opens the source at this quote in a new tab)
“Consider a choice of dopamine agonists, levodopa or monoamine oxidase B (MAO‑B) inhibitors for people in the early stages of Parkinson's disease whose motor symptoms do not impact on their quality of life.” (opens the source at this quote in a new tab)

Levodopa as the reference symptomatic therapy

“Pharmacological dopamine substitution is the mainstay of medical management of PD motor symptoms and levodopa combined with a dopa decarboxylase inhibitor (DDCI) still remains the gold-standard of symptomatic efficacy” (opens the source at this quote in a new tab)
“IPX203 was approved by the FDA in 2024 for the treatment of PD and is marketed in the US as Crexont® at levodopa dose sizes of 140 mg, 210 mg, 280 mg and 350 mg each combined with carbidopa in a ratio of 4:1.” (opens the source at this quote in a new tab)

Extended-release levodopa for motor fluctuations

“One trial evaluated the use of IPX066 for reducing OFF‐time compared with levodopa carbidopa immediate release, showing a difference between groups of 1.2 h (P < 0.0001) in favor of IPX066.” (opens the source at this quote in a new tab)
“There is insufficient evidence to support the efficacy of levodopa carbidopa controlled release to treat motor fluctuations in PD patients on (attempted) optimal oral levodopa therapy.” (opens the source at this quote in a new tab)

Effect of levodopa on disease progression: placebo-controlled trial

“The severity of parkinsonism increased more in the placebo group than in all the groups receiving levodopa: the mean difference between the total score on the UPDRS at baseline and at 42 weeks was 7.8 units in the placebo group, 1.9 units in the group receiving levodopa at a dose of 150 mg daily, 1.9 in those receiving 300 mg daily, and −1.4 in those receiving 600 mg daily (P<0.001).” (opens the source at this quote in a new tab)
“The subjects receiving the highest dose of levodopa had significantly more dyskinesia, hypertonia, infection, headache, and nausea than those receiving placebo.” (opens the source at this quote in a new tab)
“Of a total of 361 subjects enrolled in the study, 317 (88 percent) took the study medication for 40 weeks, and 311 (86 percent) completed the 2 weeks of washout (Fig. 1).” (opens the source at this quote in a new tab)
“We need to consider that a two-week washout from levodopa may have been insufficient to eliminate fully the effect of the medication on symptoms, and the results observed may be related to a profound effect of levodopa on symptoms that persists for a long time after the drug has been withdrawn.” (opens the source at this quote in a new tab)
“The clinical data suggest that levodopa either slows the progression of Parkinson’s disease or has a prolonged effect on the symptoms of the disease.” (opens the source at this quote in a new tab)
“In contrast, the neuroimaging data suggest either that levodopa accelerates the loss of nigrostriatal dopamine nerve terminals or that its pharmacologic effects modify the dopamine transporter.” (opens the source at this quote in a new tab)
“The potential long-term effects of levodopa on Parkinson’s disease remain uncertain.” (opens the source at this quote in a new tab)
“At the end of the study, when the SPECT neuroimaging studies were performed, the subjects were still taking levodopa, so it is possible to assume that levodopa has a pharmacologic effect on the dopamine transporter that interferes with and reduces the binding of the β-CIT ligand.” (opens the source at this quote in a new tab)

Characteristic	Placebo	Levodopa 150 mg/day	Levodopa 300 mg/day	Levodopa 600 mg/day	P value
Participants, no.	“90”	“92”	“88”	“91”	Not applicable
Male sex, %	“72”	“63”	“67”	“68”	“0.62”
White race, %	“90”	“91”	“93”	“88”	“0.67”
Age, years, mean ± SD	“64.9±10.3”	“64.3±10.6”	“63.8±12.1”	“65.2±10.7”	“0.84”
Duration of disease, months, mean ± SD	“5.3±5.6”	“5.7±6.1”	“7.6±7.5”	“6.0±6.1”	“0.10”
Total UPDRS score, mean ± SD	“27.7±12.0”	“27.2±12.6”	“27.5±11.6”	“29.4±13.9”	“0.63”
UPDRS motor component, mean ± SD	“18.8±8.9”	“18.6±9.1”	“18.9±8.8”	“20.5±10.8”	“0.51”
Hoehn–Yahr scale score, mean ± SD	“1.8±0.5”	“1.9±0.6”	“1.8±0.5”	“1.9±0.6”	“0.57”

Change from baseline to week 42, mean ± SD	Placebo	Levodopa 150 mg/day	Levodopa 300 mg/day	Levodopa 600 mg/day	P value for trend
Primary rater, participants, no.	“70”	“78”	“82”	“81”	Not applicable
Primary rater, total UPDRS score	“7.8±9.0”	“1.9±6.0”	“1.9±6.9”	“−1.4±7.7”	“<0.001”
Primary rater, mental component	“0.3±1.5”	“0.0±1.5”	“0.1±1.2”	“0.1±1.4”	“0.18”
Primary rater, ADL component	“2.3±3.4”	“0.5±2.3”	“0.4±2.9”	“−0.3±3.0”	“<0.001”
Primary rater, motor component	“5.2±6.4”	“1.4±5.5”	“1.4±5.3”	“−1.4±5.9”	“<0.001”
Treating investigator, total UPDRS score	“9.0±10.4”	“4.0±8.2”	“4.0±8.4”	“1.0±9.9”	“<0.001”
Treating investigator, mental component	“0.5±1.3”	“−0.1±1.4”	“0.1±1.4”	“0.1±1.6”	“0.31”
Treating investigator, ADL component	“2.5±4.0”	“0.8±3.1”	“1.0±2.8”	“0.3±3.5”	“<0.001”
Treating investigator, motor component	“6.0±7.6”	“3.2±6.4”	“3.0±6.4”	“0.6±7.7”	“<0.001”

Striatal β-CIT uptake, change from baseline to week 40	Placebo	Levodopa 150 mg/day	Levodopa 300 mg/day	Levodopa 600 mg/day	P value for dose–response
Substudy cohort, participants, no.	“29”	“33”	“37”	“36”	Not applicable
Substudy cohort, change, %, mean ± SD	“−2.6±11.3”	“−4.7±10.8”	“−3.7±9.1”	“−6.9±8.1”	“0.15”
Substudy cohort, P value compared with placebo	Not applicable	“0.46”	“0.63”	“0.11”	Not applicable
Excluding scans without dopaminergic deficit, participants, no.	“26”	“28”	“34”	“28”	Not applicable
Excluding scans without dopaminergic deficit, change, %, mean ± SD	“−1.4±10.0”	“−6.0±10.3”	“−4.0±9.4”	“−7.2±7.6”	“0.036”
Excluding scans without dopaminergic deficit, P value compared with placebo	Not applicable	“0.16”	“0.40”	“0.015”	Not applicable

Dose-dependent dyskinesia, wearing off, and other adverse events over 40 weeks of levodopa

Adverse event	Placebo (N = 90)	Levodopa 150 mg/day (N = 92)	Levodopa 300 mg/day (N = 88)	Levodopa 600 mg/day (N = 91)	P value for trend
Dyskinesia, no. (%)	“3 (3.3)”	“3 (3.3)”	“2 (2.3)”	“15 (16.5)”	“<0.001”
Dystonia, no. (%)	“19 (21.1)”	“19 (20.7)”	“14 (15.9)”	“12 (13.2)”	“0.30”
Wearing off, no. (%)	“12 (13.3)”	“15 (16.3)”	“16 (18.2)”	“27 (29.7)”	“0.06”
On–off, no. (%)	“3 (3.3)”	“1 (1.1)”	“0”	“3 (3.3)”	“0.26”
Freezing of gait, no. (%)	“13 (14.4)”	“9 (9.8)”	“6 (6.8)”	“5 (5.5)”	“0.15”
Nausea, no. (%)	“12 (13.3)”	“15 (16.3)”	“23 (26.1)”	“29 (31.9)”	“0.001”
Headache, no. (%)	“3 (3.3)”	“7 (7.6)”	“5 (5.7)”	“12 (13.2)”	“0.03”
Hypertonia, no. (%)	“1 (1.1)”	“0”	“1 (1.1)”	“5 (5.5)”	“0.03”
Infection, no. (%)	“1 (1.1)”	“0”	“0”	“6 (6.6)”	“0.01”
Dizziness, no. (%)	“6 (6.7)”	“10 (10.9)”	“5 (5.7)”	“14 (15.4)”	“0.13”
Somnolence, no. (%)	“2 (2.2)”	“0”	“5 (5.7)”	“5 (5.5)”	“0.07”
Fracture, no. (%)	“4 (4.4)”	“0”	“0”	“0”	“0.01”
Leg pain, no. (%)	“7 (7.8)”	“6 (6.5)”	“3 (3.4)”	“0”	“0.006”

“High doses, however, were associated with a greater frequency of adverse events such as dyskinesia.” (opens the source at this quote in a new tab)
“For the present, until more evidence is available, we recommend customizing the dose of levodopa to the needs of the individual patient on the basis of the clinical response and the profile of adverse events.” (opens the source at this quote in a new tab)

Effect of levodopa on disease progression: delayed-start trial

“A total of 445 patients were randomly assigned: 222 to the early-start group and 223 to the delayed-start group.” (opens the source at this quote in a new tab)
“The change in UPDRS score from baseline to week 80 was −1.0±13.1 points and −2.0±13.0 points, respectively (difference, 1.0 point; 95% confidence interval [CI], −1.5 to 3.5; P = 0.44); this finding of no significant between-group difference at week 80 implies that levodopa had no disease-modifying effect.” (opens the source at this quote in a new tab)
“The change in the UPDRS score from baseline to week 40 was −3.1±10.2 in the early-start group and 2.0±12.3 in the delayed-start group (difference, −5.1 points; 95% CI, −7.2 to −2.9), favoring the early-start group and reflecting the effect of levodopa on symptoms of the disease.” (opens the source at this quote in a new tab)
“Because of a need for symptomatic relief, 87 patients in the delayed-start group proceeded to receive the phase 2 trial medication (levodopa) before week 40, and 24 patients in the early-start group proceeded to open-label treatment with the same dose of levodopa.” (opens the source at this quote in a new tab)
“The rates of dyskinesia and levodopa-related fluctuations in motor response did not differ significantly between the two groups.” (opens the source at this quote in a new tab)
“During the first 40 weeks of the trial, the incidence of nausea was higher in the early-start group than in the delayed start-group (23.0% vs. 14.3%, P = 0.02) (Table 3).” (opens the source at this quote in a new tab)
“At 80 weeks, the percentage of patients with motor complications, including dyskinesias and fluctuations in motor response, did not differ significantly between the two groups (Table S5 in the Supplementary Appendix).” (opens the source at this quote in a new tab)
“In patients with early Parkinson’s disease, the clinical diagnosis may be incorrect in up to 15% of patients.” (opens the source at this quote in a new tab)
“Among patients with early Parkinson's disease who were evaluated over the course of 80 weeks, treatment with levodopa in combination with carbidopa had no disease-modifying effect.” (opens the source at this quote in a new tab)

Effect of levodopa on disease progression: 5-year follow-up of the delayed-start trial

“A total of 321 patients completed the 5-year visit.” (opens the source at this quote in a new tab)
“The adjusted square root transformed total Unified Parkinson’s Disease Rating Scale did not differ between treatment groups at 3 (estimated difference, 0.17; standard error, 0.13; P = 0.18) and 5 years (estimated difference, 0.24; standard error, 0.13; P = 0.07).” (opens the source at this quote in a new tab)
“We did not find a difference in disease progression or in prevalence of motor complications between patients with early PD starting treatment with a low dose of levodopa 40 weeks earlier versus 40 weeks later over the subsequent 5 years.” (opens the source at this quote in a new tab)
“A total of 413 patients (93%) still had the diagnosis PD, and 27 patients (6%) did not have PD.” (opens the source at this quote in a new tab)
“A substantial strength of the study is the high proportion of originally randomly assigned patients (77%) who completed the 5-year follow-up, minimizing the risk of bias caused by dropout.” (opens the source at this quote in a new tab)
“Another limitation is the absence of a distinction between on or off drug state (ie, wearing off) while the UPDRS motor score was administrated.” (opens the source at this quote in a new tab)
“During the study, 11 of 205 patients (5%) in the earlystart group and 22 of 213 patients (10%) in the delayed-start group died (P = 0.06).” (opens the source at this quote in a new tab)
“However, the difference in unadjusted between-group total UPDRS change score from baseline to 5 years is below the clinically important difference” (opens the source at this quote in a new tab)
“The outcomes were square root transformed due to skewness.” (opens the source at this quote in a new tab)
“An estimate higher than zero indicates a higher score in the early-start group.” (opens the source at this quote in a new tab)

Outcome	Early-start group, change from baseline, mean ± SD	Delayed-start group, change from baseline, mean ± SD	Estimated difference, square root transformed (SE)	P value
3 years, UPDRS total (I + II + III)	“2.6±11.4”	“0.9±12.8”	“0.17 (0.13)”	“0.18”
3 years, UPDRS I	“−0.2±1.8”	“−0.3±1.8”	“0.07 (0.09)”	“0.45”
3 years, UPDRS II	“1.3±4.2”	“1.1±3.7”	“0.03 (0.08)”	“0.68”
3 years, UPDRS III	“1.5±8.8”	“0.1±9.7”	“0.16 (0.11)”	“0.18”
3 years, UPDRS IV	“1.0±1.9”	“1.4±2.4”	“−0.13 (0.09)”	“0.18”
3 years, Levy A	“0.6±7.2”	“−0.4±8.1”	“0.14 (0.11)”	“0.20”
3 years, Levy B	“0.7±2.1”	“0.6±2.2”	“0.02 (0.08)”	“0.83”
5 years, UPDRS total (I + II + III)	“11.5±17.0”	“8.2±16.2”	“0.24 (0.13)”	“0.07”
5 years, UPDRS I	“0.4±2.2”	“0.2±1.9”	“0.11 (0.08)”	“0.17”
5 years, UPDRS II	“3.7±4.7”	“3.2±5.3”	“0.09 (0.08)”	“0.25”
5 years, UPDRS III	“7.4±13.7”	“4.7±11.9”	“0.21 (0.12)”	“0.09”
5 years, UPDRS IV	“2.4±2.9”	“2.2±2.4”	“<0.01 (0.09)”	“0.97”
5 years, Levy A	“4.7±10.9”	“2.9±9.4”	“0.15 (0.12)”	“0.20”
5 years, Levy B	“2.1±3.0”	“1.5±2.4”	“0.11 (0.08)”	“0.16”

Timing of levodopa initiation and motor complications: meta-analysis

“Seven studies with a total of 1149 patients (636 in the early-start group and 513 in the delayed-start) were included in our analysis.” (opens the source at this quote in a new tab)
“There was no difference between groups regarding motor complications (OR 1.39; 95% CI: 0.68-1.72; P = 0.37) or dyskinesias (OR 1.52; 95% CI: 0.90-2.57; P = 0.11).” (opens the source at this quote in a new tab)
“Delaying treatment with levodopa does not seem to prevent levodopa-related motor complications in PD.” (opens the source at this quote in a new tab)

Initial levodopa compared with levodopa-sparing therapy: evidence-based review conclusions

“Of importance, these studies showed superior benefit of levodopa over DAs in improving motor scores and, where assessed, quality of life, and significantly more nonmotor side effects have been reported with DAs.” (opens the source at this quote in a new tab)
“In addition, in longer term follow-up, the available evidence suggests that there is no clinically relevant difference on motor function, troublesome motor complications, or mortality according to the choice of initial therapy.” (opens the source at this quote in a new tab)
“Factors to be taken into account include the higher risk of motor complications in younger onset patients and personal circumstances.” (opens the source at this quote in a new tab)
“These may include the need for rapid improvement, for example, for reasons of employment (which would favor initial levodopa) or the predominant need or desire to delay dyskinesia for as long as possible (which favors levodopa-sparing initial treatments).” (opens the source at this quote in a new tab)

Levodopa compared with levodopa-sparing initial therapy: pragmatic trial

“Between Nov 9, 2000, and Dec 22, 2009, 1620 patients were assigned to study groups (528 to levodopa, 632 to dopamine agonist, 460 to MAOBI).” (opens the source at this quote in a new tab)
“With 3-year median follow-up, PDQ-39 mobility scores averaged 1·8 points (95% CI 0·5–3·0, p=0·005) better in patients randomly assigned to levodopa than those assigned to levodopa-sparing therapy, with no increase or attrition of benefit during 7 years’ observation.” (opens the source at this quote in a new tab)
“Very small but persistent benefits are shown for patient-rated mobility scores when treatment is initiated with levodopa compared with levodopa-sparing therapy.” (opens the source at this quote in a new tab)
“Patients in the levodopa group were more likely to develop dyskinesias than those in the levodopa-sparing group (hazard ratio [HR] 1·52, 95% CI 1·16–2·00, p=0·003; figure 5), but there was no difference in motor fluctuations (1·11, 0·90–1·37, p=0·3; appendix).” (opens the source at this quote in a new tab)
“Thus, the benefits of levodopa compared with levodopa-sparing are unquestionably small.” (opens the source at this quote in a new tab)
“Thus, there seem to be no grounds for concerns that use of levodopa as first-line therapy results in worse long-term outcome.” (opens the source at this quote in a new tab)