- carbidopa monohydrate
POM: Prescription only medicine
This information is intended for use by health professionals
Excipient with known effect:Each film-coated tablet contains 0.78mg lecithin (soya) (E322).For the full list of excipients, see section 6.1.
PosologyThe optimum daily dose must be determined by careful titration of levodopa in each patient. The daily dose should be preferably optimised using one of the seven available tablet strengths (50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg, 100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg, 150 mg/37.5 mg/200 mg, 175 mg/43.75 mg/ 200 mg or 200 mg/50 mg/200 mg levodopa/carbidopa/entacapone). Patients should be instructed to take only one Sastravi tablet per dose administration. Patients receiving less than 70-100 mg carbidopa a day are more likely to experience nausea and vomiting. While the experience with total daily dose greater than 200 mg carbidopa is limited, the maximum recommended daily dose of entacapone is 2,000 mg and therefore the maximum dose is 10 tablets per day for the Sastravi strengths of 50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg, 100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg and 150 mg/37.5 mg/200 mg. Ten tablets of Sastravi 150 mg/37.5 mg/200 mg equals 375 mg of carbidopa a day. According to this daily carbidopa dose, the maximum recommended daily 175 mg/43.75 mg/ 200 mg dose is 8 tablets per day and Sastravi 200 mg/50 mg/200 mg dose is 7 tablets per day.Usually Sastravi is to be used in patients who are currently treated with corresponding doses of standard release levodopa/DDC inhibitor and entacapone.How to transfer patients taking levodopa/DDC inhibitor (carbidopa or benserazide) preparations and entacapone tablets to Sastravia. Patients who are currently treated with entacapone and with standard release levodopa/carbidopa in doses equal to Sastravi tablet strengths can be directly transferred to corresponding Sastravi tablets.For example, a patient taking one tablet of 50 mg/12.5 mg of levodopa/carbidopa with one tablet of entacapone 200 mg four times daily can take one 50 mg/12.5 mg/200 mg Sastravi tablet four times daily in place of their usual levodopa/carbidopa and entacapone doses. b. When initiating Sastravi therapy for patients currently treated with entacapone and levodopa/carbidopa in doses not equal to Sastravi 50 mg/12.5 mg/200 mg (or 75 mg/18.75 mg/200 mg or 100 mg/25 mg/200 mg or 125 mg/31.25 mg/200 mg or 150 mg/37.5 mg/200 mg or 175 mg/43.75 mg/200 mg or 200 mg/50 mg/200 mg) tablets, Sastravi dosing should be carefully titrated for optimal clinical response. At the initiation, Sastravi should be adjusted to correspond as closely as possible to the total daily dose of levodopa currently used.c. When initiating Sastravi in patients currently treated with entacapone and levodopa/benserazide in a standard release formulation, the dosing of levodopa/benserazide should be discontinued in the previous night, and Sastravi should be started in the next morning. The starting dose of Sastravi should provide either the same amount of levodopa or slightly (5-10%) more.How to transfer patients not currently treated with entacapone to SastraviInitiation of Sastravi may be considered at corresponding doses to current treatment in some patients with Parkinson's disease and end-of-dose motor fluctuations, who are not stabilised on their current standard release levodopa/DDC inhibitor treatment. However, a direct switch from levodopa/DDC inhibitor to Sastravi is not recommended for patients who have dyskinesias or whose daily levodopa dose is above 800 mg. In such patients it is advisable to introduce entacapone treatment as a separate treatment (entacapone tablets) and adjust the levodopa dose if necessary, before switching to Sastravi.Entacapone enhances the effects of levodopa. It may therefore be necessary, particularly in patients with dyskinesia, to reduce levodopa dose by 10-30% within the first days to first weeks after initiating Sastravi treatment. The daily dose of levodopa can be reduced by extending the dosing intervals and/or by reducing the amount of levodopa per dose, according to the clinical condition of the patient.
Dose adjustment during the course of the treatmentWhen more levodopa is required, an increase in the frequency of doses and/or the use of an alternative strength of Sastravi should be considered, within the dose recommendations.When less levodopa is required, the total daily dose of Sastravi should be reduced either by decreasing the frequency of administration by extending the time between doses, or by decreasing the strength of Sastravi at an administration.If other levodopa products are used concomitantly with a Sastravi tablet, the maximum dose recommendations should be followed.Discontinuation of Sastravi therapy: If Sastravi treatment (levodopa/carbidopa/entacapone) is discontinued and the patient is transferred to levodopa/DDC inhibitor therapy without entacapone, it is necessary to adjust the dosing of other antiparkinsonian treatments, especially levodopa, to achieve a sufficient level of control of the parkinsonian symptoms.Paediatric population: The safety and efficacy of Sastravi in children aged below 18 years have not been established. No data are available.Older people: No dose adjustment of Sastravi is required for older patients.Patients with hepatic impairment: It is advised that Sastravi should be administered cautiously to patients with mild to moderate hepatic impairment. Dose reduction may be needed (see section 5.2). For severe hepatic impairment see section 4.3.Patients with renal impairment: Renal impairment does not affect the pharmacokinetics of entacapone. No particular studies are reported on the pharmacokinetics of levodopa and carbidopa in patients with renal insufficiency, therefore Sastravi therapy should be administered cautiously to patients in severe renal impairment including those receiving dialysis therapy (see section 5.2).
Method of administrationEach tablet is to be taken orally either with or without food (see section 5.2). One tablet contains one treatment dose and the tablet may only be administered as whole tablets.
- Dopamine Dysregulation Syndrome (DDS) is an addictive disorder resulting in excessive use of the product seen in some patients treated with carbidopa/ levodopa. Before initiation of treatment, patients and caregivers should be warned of the potential risk of developing DDS (see also section 4.8).- Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments containing levodopa including Sastravi. Review of treatment is recommended if such symptoms develop.- For patients who experience progressive anorexia, asthenia and weight decrease within a relatively short period of time, a general medical evaluation including liver function should be considered.- Levodopa/carbidopa may cause false positive result when a dipstick is used to test for urinary ketone; and this reaction is not altered by boiling the urine sample. The use of glucose oxidase methods may give false negative results for glycosuria.
PregnancyThere are no adequate data from the use of the combination of levodopa/carbidopa/entacapone in pregnant women. Studies in animals have shown reproductive toxicity of the separate compounds (see section 5.3). The potential risk for humans is unknown. Sastravi should not be used during pregnancy unless the benefits for the mother outweigh the possible risks to the foetus.
BreastfeedingLevodopa is excreted in human breast milk. There is evidence that breastfeeding is suppressed during treatment with levodopa. Carbidopa and entacapone were excreted in milk in animals but is not known whether they are excreted in human breast milk. The safety of levodopa, carbidopa or entacapone in the infant is not known. Women should not breast-feed during treatment with Sastravi.
FertilityNo adverse reactions on fertility were observed in preclinical studies with entacapone, carbidopa or levodopa alone. Fertility studies in animals have not been conducted with the combination of entacapone, levodopa and carbidopa.
a. Summary of the safety profileThe most frequently reported adverse reactions with levodopa/carbidopa/entacapone are dyskinesias occurring in approximately 19% of patients; gastrointestinal symptoms including nausea and diarrhoea occurring in approximately 15% and 12% of patients, respectively; muscle, musculoskeletal and connective tissue pain occurring in approximately 12% of patients; and harmless reddish-brown discolouration of urine (chromaturia) occurring in approximately 10% of patients. Serious events of gastrointestinal haemorrhage (uncommon) and angioedema (rare) have been identified from the clinical trials with levodopa/carbidopa/entacapone or entacapone combined with levodopa/DDC inhibitor. Serious hepatitis with mainly cholestatic features, rhabdomyolysis and neuroleptic malignant syndrome may occur with levodopa/carbidopa/entacapone although no cases have been identified from the clinical trial data.
b. Tabulated list of adverse reactionsThe following adverse reactions, listed in Table 1, have been accumulated both from a pooled data of eleven double-blind clinical trials consisting of 3230 patients (1810 treated with levodopa/carbidopa/entacapone or entacapone combined with levodopa/DDC inhibitor, and 1420 treated with placebo combined with levodopa/DDC inhibitor or cabergoline combined with levodopa/ DDC inhibitor), and from the post-marketing data since the introduction of entacapone into the market for the combination use of entacapone with levodopa/DDC inhibitor.Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data, since no valid estimate can be derived from clinical trials or epidemiological studies).
|Table 1. Adverse reactions|
|Blood and lymphatic system disorders|
|Metabolism and nutrition disorders|
|Common:||Weight decreased*, decreased appetite*|
|Common:||Depression, hallucination, confusional state*, abnormal dreams*, anxiety, insomnia|
|Uncommon :||Psychosis, agitation*|
|Not known:||Suicidal behaviour, Dopamine dysregulation syndrome|
|Nervous system disorders|
|Common:||Parkinsonism aggravated (e.g. bradykinesia)*, tremor, on and off phenomenon, dystonia, mental impairment (e.g. memory impairment, dementia), somnolence, dizziness*, headache|
|Not known:||Neuroleptic malignant syndrome*|
|Common:||Ischemic heart disease events other than myocardial infarction (e.g. angina pectoris)**, irregular heart rhythm|
|Common:||Orthostatic hypotension, hypertension|
|Respiratory, thoracic and mediastinal disorders|
|Very common:||Diarrhoea*, nausea*|
|Common:||Constipation*, vomiting*, dyspepsia, abdominal pain and discomfort*, dry mouth*|
|Uncommon:||Hepatic function test abnormal*|
|Not known:||Hepatitis with mainly cholestatic features (see section 4.4)*|
|Skin and subcutaneous tissue disorders|
|Uncommon:||Discolourations other than urine (e.g. skin, nail, hair, sweat)*|
|Musculoskeletal and connective tissue disorders|
|Very common:||Muscle, musculoskeletal and connective tissue pain*|
|Common:||Muscle spasms, arthralgia|
|Renal and urinary disorders|
|Common:||Urinary tract infection|
|General disorders and administration site conditions|
|Common:||Chest pain, peripheral oedema, fall, gait disturbance, asthenia, fatigue|
c. Description of selected adverse reactionsAdverse reactions that are mainly attributable to entacapone or are more frequent with entacapone than levodopa/DDC inhibitor alone are indicated with an asterisk in Table 1, section 4.8b. Some of these adverse reactions relate to the increased dopaminergic activity (e.g. dyskinesia, nausea and vomiting) and occur most commonly at the beginning of the treatment. Reduction of levodopa dose decreases the severity and frequency of these dopaminergic reactions. Few adverse reactions are known to be directly attributable to the active substance entacapone including diarrhoea and reddish-brown discolouration of urine. Entacapone may in some cases cause also discolouration of e.g. skin, nail, hair and sweat. Other adverse reactions with an asterisk in Table 1, section 4.8b are marked based on either their more frequent occurring (by the frequency difference of at least 1%) in the clinical trial data with entacapone than levodopa/DDCI alone or the individual case safety reports received after the introduction of entacapone into the market.Convulsions have occurred rarely with levodopa/carbidopa; however a causal relationship to levodopa/carbidopa therapy has not been established.
Dopamine Dysregulation Syndrome (DDS) is an addictive disorder seen in some patients treated with carbidopa/ levodopa. Affected patients show a compulsive pattern of dopaminergic drug misuse above doses adequate to control motor symptoms, which may in some cases result in severe dyskinesias (see also section 4.4).Impulse control disorders: Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments containing levodopa including Sastravi (see section 4.4).Entacapone in association with levodopa has been associated with isolated cases of excessive daytime somnolence and sudden sleep onset episodes.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Mechanism of actionAccording to the current understanding, the symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Dopamine does not cross the blood-brain barrier. Levodopa, the precursor of dopamine, crosses the blood brain barrier and relieves the symptoms of the disease. As levodopa is extensively metabolised in the periphery, only a small portion of a given dose reaches the central nervous system when levodopa is administered without metabolic enzyme inhibitors.
Pharmacodynamic effectsCarbidopa and benserazide are peripheral DDC inhibitors which reduce the peripheral metabolism of levodopa to dopamine, and thus, more levodopa is available to the brain. When decarboxylation of levodopa is reduced with the co-administration of a DDC inhibitor, a lower dose of levodopa can be used and the incidence of adverse reactions such as nausea is reduced.With inhibition of the decarboxylase by a DDC inhibitor, catechol-O-methyltransferase (COMT) becomes the major peripheral metabolic pathway catalyzing the conversion of levodopa to 3-O-methyldopa (3-OMD), a potentially harmful metabolite of levodopa. Entacapone is a reversible, specific and mainly peripherally acting COMT inhibitor designed for concomitant administration with levodopa. Entacapone slows the clearance of levodopa from the bloodstream resulting in an increased area under the curve (AUC) in the pharmacokinetic profile of levodopa. Consequently the clinical response to each dose of levodopa is enhanced and prolonged.
Clinical efficacy and safetyThe evidence of the therapeutic effects of levodopa/carbidopa/entacapone is based on two phase III double-blind studies, in which 376 Parkinson's disease patients with end-of-dose motor fluctuations received either entacapone or placebo with each levodopa/DDC inhibitor dose. Daily ON time with and without entacapone was recorded in home-diaries by patients. In the first study, entacapone increased the mean daily ON time by 1 h 20 min (CI 95% 45 min, 1 h 56 min) from baseline. This corresponded to an 8.3% increase in the proportion of daily ON time. Correspondingly, the decrease in daily OFF time was 24% in the entacapone group and 0% in the placebo group. In the second study, the mean proportion of daily ON time increased by 4.5% (CI95% 0.93%, 7.97%) from baseline. This is translated to a mean increase of 35 min in the daily ON time. Correspondingly, the daily OFF time decreased by 18% on entacapone and by 5% on placebo. Because the effects of levodopa/carbidopa/entacapone tablets are equivalent with entacapone 200 mg tablet administered concomitantly with the commercially available standard release carbidopa/levodopa preparations in corresponding doses these results are applicable to describe the effects of levodopa/carbidopa/entacapone as well.
General characteristics of the active substances
AbsorptionThere are substantial inter- and intra-individual variations in the absorption of levodopa, carbidopa and entacapone. Both levodopa and entacapone are rapidly absorbed and eliminated. Carbidopa is absorbed and eliminated slightly slower compared with levodopa. When given separately without the two other active substances, the bioavailability for levodopa is 15-33%, for carbidopa 40-70% and for entacapone 35% after a 200 mg oral dose. Meals rich in large neutral amino acids may delay and reduce the absorption of levodopa. Food does not significantly affect the absorption of entacapone.
DistributionThe distribution volume of both levodopa (Vd 0.36-1.6 l/kg) and entacapone (Vdss 0.27 l/kg) is moderately small while no data for carbidopa are available.Levodopa is bound to plasma protein only to a minor extent of about 10-30% and carbidopa is bound approximately 36%, while entacapone is extensively bound to plasma proteins (about 98%) mainly to serum albumin. At therapeutic concentrations, entacapone does not displace other extensively bound active substances (e.g. warfarin, salicylic acid, phenylbutazone, or diazepam), nor is it displaced to any significant extent by any of these substances at therapeutic or higher concentrations.
BiotransformationLevodopa is extensively metabolised to various metabolites: decarboxylation by dopa decarboxylase (DDC) and O-methylation by catechol-O-methyltransferase (COMT) being the most important pathways.Carbidopa is metabolized to two main metabolites which are excreted in the urine as glucuronides and unconjugated compounds. Unchanged carbidopa accounts for 30% of the total urinary excretion.Entacapone is almost completely metabolized prior to excretion via urine (10 to 20%) and bile/faeces (80 to 90%). The main metabolic pathway is glucuronidation of entacapone and its active metabolite, the cis-isomer, which accounts for about 5% of plasma total amount.
EliminationTotal clearance for levodopa is in the range of 0.55-1.38 l/kg/h and for entacapone is in the range of 0.70 l/kg/h. The elimination-half life is (t1/2) is 0.6-1.3 hours for levodopa, 2-3 hours for carbidopa and 0.4-0.7 hours for entacapone, each given separately.Due to short elimination half-lives, no true accumulation of levodopa or entacapone occurs on repeated administration.Data from in vitro studies using human liver microsomal preparations indicate that entacapone inhibits cytochrome P450 2C9 (IC50 ~ 4 μM). Entacapone showed little or no inhibition of other types of P450 isoenzymes (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19); see section 4.5.
Older people:When given without carbidopa and entacapone, the absorption of levodopa is greater and elimination is slower in older subjects than in young subjects. However, after combination of carbidopa with levodopa, the absorption of levodopa is similar between the older and the young, but the AUC is still 1.5 fold greater in the older people due to decreased DDC activity and lower clearance by aging. There are no significant differences in the AUC of carbidopa or entacapone between younger (4564 years) and older subjects (6575 years).
GenderBioavailability of levodopa is significantly higher in women than in men. In the pharmacokinetic studies with levodopa/carbidopa/entacapone the bioavailability of levodopa is higher in women than in men primarily due to the difference in body weight, while there is no gender difference with carbidopa and entacapone.
Hepatic impairmentThe metabolism of entacapone is slowed in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) leading to an increased plasma concentration of entacapone both in the absorption and elimination phases (see sections 4.2 and 4.3). No particular studies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic impairment are reported, however, it is advised that Sastravi should be administered cautiously to patients with mild or moderate hepatic impairment.
Renal impairmentRenal impairment does not affect the pharmacokinetics of entacapone. No particular studies are reported on the pharmacokinetics of levodopa and carbidopa in patients with renal impairment. However, a longer dosing interval of Sastravi may be considered for patients who are receiving dialysis therapy (see section 4.2).
Tablet core:Croscarmellose sodiumHydroxypropylcelluloseTrehalose dihydrateCellulose, powderedSodium sulfate, anhydrousCellulose, microcrystallineMagnesium stearate
Film coat:Polyvinyl alcohol-part. hydrolyzedTalcTitanium dioxide (E171)MacrogolIron oxide red (E172)Lecithin (soya) (E322)Iron oxide yellow (E172)
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