Levodopa + enzyme inhibitor (benserazide, carbidopa, entacapone)Classification: C!
Drug products: Carbidopa And Levodopa, Carbidopa/Levodopa Fair-Med, Comtess®, Dazonay, Duodopa®, Entacapone Mylan, Entacapone Orion, Entacapone Teva, Flexilev, Karbidopa/Levodopa Ebb, Lecigon, Levocar, Levodopa/Benserazid 2care4, Levodopa/Benserazid Ebb, Levodopa/Benserazid Orifarm, Levodopa/Benserazid ratiopharm, Levodopa/Benserazide Orifarm, Levodopa/Carbidopa Accord, Levodopa/Carbidopa ratiopharm, Levodopa/Carbidopa/Entacapone Accord, Levodopa/Carbidopa/Entacapone Orion, Levodopa/Carbidopa/Entacapone Rivopharm, Lodosyn, Madopar, Madopar Depot, Madopar Quick, Madopar Quick mite, Madopark, Madopark Depot, Madopark®, Madopark® Depot, Madopark® Quick, Madopark® Quick mite, Pentiro, Sastravi, Sinemet, Sinemet®, Sinemet® Depot, Sinemet® Depot Mite, Stalevo®
ATC code: N04BA, N04BA02, N04BA03, N04BX02
Women with Parkinson’s disease often need lower doses of levodopa than men. Dyskinesia is more common and the delay between start of treatment and development of dyskinesia is shorter in women. Levodopa + enzyme inhibitors is also used in treatment of Restless Legs Syndrome (RLS). One study has shown that there was no sex difference in increased level of symptoms (augmentation) with continuous use. Studies have shown that benserazide 125 mg and carbidopa 250 mg given in the same doses to men and women increase serum prolactin more in women than in men.
The reported incidence and prevalence of Parkinson’s disease (PD) is slightly higher in men than in women. It seems that men develop PD earlier in life compared to women. Several possible explanations behind these sex differences have been suggested; the protective role of estrogens in premenopausal women, and different profiles of risk factors (environmental and/or genetic). Sex differences in clinical presentations of PD have also been reported. Since the activities of daily living might differ between men and women with PD, different treatment strategies can be recommended to men and women with PD .
Pharmacokinetics and dosing
Several studies have shown that women have a higher levodopa AUC than men when receiving a standard dose of 250 mg levodopa corrected as mg/kg body weight, leading to a higher bioavailability of levodopa. This may be explained by the generally lower body weight of women [2-4]. Contrary to these findings, other studies have shown greater bioavailability in women even after adjustment for body weight [5-7]. In these studies, patients received an oral dose of 100 mg levodopa plus 25 mg benserazide or 10 mg carbidopa. Also, levodopa AUC adjusted for body weight were higher in women [5-7].
In a Swedish registry study, women used a lower mean daily dose of levodopa than men . Similar findings were observed in a clinic-based studies from the US and Brazil [9, 10]. A reason behind this sex difference could be the metabolic differences and the risk of side effects such as dyskinesia (see Adverse effects).
No studies with a clinically relevant sex analysis regarding effects of levodopa + enzyme inhibitors have been found.
Women with PD seem to be at higher risk of dyskinesia, due to pharmacokinetic factors. This is, however, not confirmed in other reports where patient’s sex has been studied as a risk factor . In one clinical study (67 men, 49 women) no difference in the proportion of men and women experiencing dyskinesias was observed . Female sex is associated with a significantly shorter time to occurrence of levodopa-induced dyskinesia (LID) [11, 12]. The median time to LID was 4 years for women and 6 years for men. The reason for the sex difference is unclear. It has been suggested that hormonal status may underlie this susceptibility, possibly by modifying the individual dyskinetic sensitivity to levodopa through estrogens [11, 12]. Women have a lower expression of dopamine receptor genetic polymorphism (DRD2) which seems to exert a protective role in men against dyskinesia . Women with PD have an 87% higher binding capacity of levodopa in the prefrontal cortex compared to men .
Dopaminergic medication is also used as a treatment for RLS (Restless Legs Syndrome) and PLMS (Periodic Leg Movement Syndrome). For nightly treatments, a problem with morning end-of-dose rebound increase in leg movements are reported to occur in about 25% of the patients. In one study (25 men, 21 women), patients with either RLS or PLMS were given 0.5-1 tablet levodopa/carbidopa 100/25 mg 20–30 minutes before bedtime. The dose was increased by 0.5 tablet every 3 days until satisfactory sleep occurred for the first 3 hours or the dose reached a maximum of 4 tablets. Augmentation (increased symptoms over time) was greater for patients with more severe RLS symptoms and for patients on higher doses (>200/50 mg) but was unrelated to patient’s sex or age .
Studies report that the increase in serum prolactin after receiving carbidopa or benserazide is larger in women than in men. In one study, healthy young men and women were given a single 125 mg oral dose benserazide inducing a larger percent increase of serum prolactin in women compared to men. In the general population, prolactin secretion is more affected by various stimuli in women . In a similar study, benserazide was given in doses ranging between 10–125 mg and carbidopa was given in doses ranging between 10–250 mg to different groups of women . Two different groups of men were given 125 mg of benserazide and 250 mg of carbidopa, respectively. Significant prolactin rises were observed in both men and women for all doses tested. Secretion areas were lager in women than in men and peak values were higher in women than in men. This sex-related finding is not unexpected considering the well-known sex-related differences in both spontaneous blood levels and responses to various stimuli. Sex differences may also influence serotonergic regulation of prolactin secretion . For entacapone, pre-marketing clinical trials did not note any differences in the rate of adverse events attributable to entacapone by patient’s sex .
Reproductive health issues
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2019-11-27
- Georgiev D, Hamberg K, Hariz M, Forsgren L, Hariz GM. Gender differences in Parkinson's disease: A clinical perspective. Acta Neurol Scand. 2017;136(6):570-584. PubMed
- Arabia G, Zappia M, Bosco D, Crescibene L, Bagalà A, Bastone L et al. Body weight, levodopa pharmacokinetics and dyskinesia in Parkinson's disease. Neurol Sci. 2002;23 Suppl 2:S53-4. PubMed
- Sharma JC, Bachmann CG, Linazasoro G. Classifying risk factors for dyskinesia in Parkinson's disease. Parkinsonism Relat Disord. 2010;16:490-7. PubMed
- Zappia M, Crescibene L, Arabia G, Nicoletti G, Bagalà A, Bastone L et al. Body weight influences pharmacokinetics of levodopa in Parkinson's disease. Clin Neuropharmacol. 2002;25:79-82. PubMed
- Kompoliti K, Adler CH, Raman R, Pincus JH, Leibowitz MT, Ferry JJ et al. Gender and pramipexole effects on levodopa pharmacokinetics and pharmacodynamics. Neurology. 2002;58(9):1418-22. PubMed
- Martinelli P, Contin M, Scaglione C, Riva R, Albani F, Baruzzi A. Levodopa pharmacokinetics and dyskinesias: are there sex-related differences?. Neurol Sci. 2003;24:192-3. PubMed
- Kumagai T, Nagayama H, Ota T, Nishiyama Y, Mishina M, Ueda M. Sex differences in the pharmacokinetics of levodopa in elderly patients with Parkinson disease. Clin Neuropharmacol. 2014;37(6):173-6. PubMed
- Nyholm D, Karlsson E, Lundberg M, Askmark H. Large differences in levodopa dose requirement in Parkinson's disease: men use higher doses than women. Eur J Neurol. 2010;17:260-6. PubMed
- Baba Y, Putzke JD, Whaley NR, Wszolek ZK, Uitti RJ. Gender and the Parkinson's disease phenotype. J Neurol. 2005;252:1201-5. PubMed
- Altmann V, Schumacher-Schuh AF, Rieck M, Callegari-Jacques SM, Rieder CR, Hutz MH. Influence of genetic, biological and pharmacological factors on levodopa dose in Parkinson's disease. Pharmacogenomics. 2016;17(5):481-8. PubMed
- Hassin-Baer S, Molchadski I, Cohen OS, Nitzan Z, Efrati L, Tunkel O et al. Gender effect on time to levodopa-induced dyskinesias. J Neurol. 2011;258:2048-53. PubMed
- Zappia M, Annesi G, Nicoletti G, Arabia G, Annesi F, Messina D et al. Sex differences in clinical and genetic determinants of levodopa peak-dose dyskinesias in Parkinson disease: an exploratory study. Arch Neurol. 2005;62:601-5. PubMed
- Kaasinen V, Nurmi E, Brück A, Eskola O, Bergman J, Solin O et al. Increased frontal [(18)F]fluorodopa uptake in early Parkinson's disease: sex differences in the prefrontal cortex. Brain. 2001;124:1125-30. PubMed
- Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep. 1996;19:205-13. PubMed
- Murialdo G, Masturzo P, Carolei A, Polleri A. Dose and sex related effects of benserazide on prolactin secretion. Boll Soc Ital Biol Sper. 1979;55:373-7. PubMed
- Polleri A, Masturzo P, Murialdo G, Carolei A. Dose and sex related effects of aromatic aminoacids decarboxylase inhibitors on serum prolactin in humans. Acta Endocrinol (Copenh). 1980;93:7-12. PubMed
- Stalevo (levodopa, carbidopa, entacapone). DailyMed [www]. [updated 2020-01-07, cited 2020-01-16]. länk
- Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2019 [cited 2020-03-10.] länk
Reviewed by: Mia von Euler, Carl-Olav Stiller, Diana Rydberg
Approved by: Karin Schenck-Gustafsson