SASTRAVI

Posology The optimum daily dose must be determined by careful titration of levodopa in each patient. 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. 5 mg/200 mg. 5 mg/200 mg equals 375 mg of carbidopa a day. 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 Sastravi a.

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. 5 mg/200 mg Sastravi tablet four times daily in place of their usual levodopa/carbidopa and entacapone doses.

b. 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 Sastravi Initiation 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 treatment When 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.

Elderly:

No dose adjustment of Sastravi is required for elderly.

Hepatic impairment:

It is advised that Sastravi should be administered cautiously to patients with mild to moderate hepatic impairment. 2). For severe hepatic impairment see section

a. Summary of the safety profile The 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 reactions The 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. g. g. g. g. skin, nail, hair, sweat)* Rare: Angioedema Not known: Urticaria* Musculoskeletal and connective tissue disorders Very common: Muscle, musculoskeletal and connective tissue pain* Common: Muscle spasms, arthralgia Not known: Rhabdomyolysis* Renal and urinary disorders Very common: Chromaturia* Common: Urinary tract infection Uncommon: Urinary retention General disorders and administration site conditions Common: Chest pain, peripheral oedema, fall, gait disturbance, asthenia, fatigue Uncommon: Malaise *Adverse reactions that are mainly attributable to entacapone or are more frequent (by the frequency difference of at least 1% in the clinical trial data) with entacapone than levodopa/DDC inhibitor alone.

See section c. 54%, respectively) are derived from an analysis of 13 double- blind studies involving 2082 patients with end-of-dose motor fluctuations receiving entacapone. c. 8b. 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.

g. skin, nail, hair and sweat. 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. 4). Dopamine Dysregulation Syndrome (DDS) is an addictive disorder seen in some patients treated […]

Sastravi is not recommended for the treatment of drug-induced extrapyramidal reactions - Sastravi therapy should be administered cautiously to patients with ischemic heart disease, severe cardiovascular or pulmonary disease, bronchial asthma, renal or endocrine disease, history of peptic ulcer disease or history of convulsions.

- In patients with a history of myocardial infarction who have residual atrial nodal or ventricular arrhythmias; cardiac function should be monitored with particular care during the period of initial dose adjustments. - All patients treated with Sastravi should be monitored carefully for the development of mental changes, depression with suicidal tendencies, and other serious antisocial behaviour.

Patients with past or current psychosis should be treated with caution. - Concomitant administration of antipsychotics with dopamine receptor- blocking properties, particularly D2 receptor antagonists should be carried out with caution, and the patient carefully observed for loss of antiparkinsonian effect or worsening of parkinsonian symptoms.

- Patients with chronic wide-angle glaucoma may be treated with Sastravi with caution, provided the intra-ocular pressure is well controlled and the patient is monitored carefully for changes in intra-ocular pressure. - Sastravi may induce orthostatic hypotension.

Therefore Sastravi should be given cautiously to patients who are taking other medicinal products which may cause orthostatic hypotension. 7). g. dyskinesia, were more common in patients who received entacapone and dopamine agonists (such as bromocriptine), selegiline or amantadine compared to those who received placebo with this combination.

The doses of other antiparkinsonian medicinal products may need to be adjusted when Sastravi treatment is substituted for a patient currently not treated with entacapone. - Rhabdomyolysis secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS) has been observed rarely in patients with Parkinson's disease.

Therefore, any abrupt dose reduction or withdrawal of levodopa should be carefully observed, particularly in patients who are also receiving neuroleptics. g. agitation, confusion, coma), hyperthermia, autonomic dysfunction (tachycardia, labile blood pressure) and elevated serum creatine phosphokinase.

In individual cases, only some of these symptoms and/or findings may be evident. The early diagnosis is important for the appropriate management of NMS. A syndrome resembling the neuroleptic malignant syndrome including muscular rigidity, elevated body temperature, mental changes and increased serum creatine phosphokinase has been reported with the abrupt withdrawal of antiparkinsonian agents.

Neither NMS nor rhabdomyolysis have been reported in association with entacapone treatment from controlled trials in which entacapone was discontinued abruptly. Since the introduction of entacapone into the market, isolated cases of NMS have been reported, especially following abrupt reduction or discontinuation of entacapone and other concomitant dopaminergic medicinal products.

When considered necessary, the replacement of Sastravi with levodopa and DDC inhibitor without entacapone or other dopaminergic treatment should proceed slowly and an increase in levodopa dose may be necessary. - If general anaesthesia is required, therapy with Sastravi may be continued for as long as the patient is permitted to take fluids and medicinal products by mouth.

If therapy has to be stopped temporarily, Sastravi may be restarted as soon as oral medicinal products can be taken at the same daily dose as before. - Periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function is recommended during extended therapy with Sastravi.

- For patients experiencing diarrhoea, a follow-up of weight is recommended in order to avoid potential excessive weight decrease. Prolonged or persistent diarrhoea appearing during use of entacapone may be a sign of colitis. In the event of prolonged or persistent diarrhoea, the drug should be discontinued and appropriate medical therapy and investigations considered.

- 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. - Dopamine Dysregulation Syndrome (DDS) is an addictive disorder resulting in excessive use of the product seen in some patients treated with carbidopa/ levodopa. 8). - 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.

Sodium This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially ‘sodium-free’.

3.

Renal impairment:

Renal impairment does not affect the pharmacokinetics of entacapone. 2). 2). One tablet contains one treatment dose and the tablet may only be administered as whole tablets. 1 or soya or peanut. - Severe hepatic impairment. - Narrow-angle glaucoma.

- Pheochromocytoma. g. phenelzine, tranylcypromine). 5). - A previous history of Neuroleptic Malignant Syndrome (NMS) and/or non- traumatic rhabdomyolysis.