Adverse reactions : תופעות לוואי

4.8 Undesirable effects
a. Summary of the safety profile
The most frequently reported adverse reactions with Stalevo 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 Stalevo or entacapone combined with levodopa/DDC inhibitor. Serious hepatitis with mainly cholestatic features, rhabdomyolysis and neuroleptic malignant syndrome may occur with Stalevo 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 Stalevo 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
Common:                  Anaemia
Uncommon:                Thrombocytopenia

Metabolism and nutrition disorders
Common:                    Weight decreased*, decreased appetite*
Psychiatric disorders
Common:                    Depression, hallucination, confusional state*, abnormal dreams*, anxiety, insomnia
Uncommon:                  Psychosis, agitation*
Not known:                 Suicidal behaviour, Dopamine dysregulation syndrome Nervous system disorders
Very common:               Dyskinesia*
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*
Eye disorders
Common:                    Blurred vision
Cardiac disorders
Common:                    Ischemic heart disease events other than myocardial infarction (e.g.
angina pectoris)**, irregular heart rhythm
Uncommon:                  Myocardial infarction**
Vascular disorders
Common:                    Orthostatic hypotension, hypertension
Uncommon:                  Gastrointestinal haemorrhage
Respiratory, thoracic and mediastinal disorders
Common:                    Dyspnoea
Gastrointestinal disorders
Very common:               Diarrhoea*, nausea*
Common:                    Constipation*, vomiting*, dyspepsia, abdominal pain and discomfort*, dry mouth*
Uncommon:                  Colitis*, dysphagia
Hepatobiliary disorders
Uncommon:                  Hepatic function test abnormal*
Not known:                 Hepatitis with mainly cholestatic features (see section 4.4)* Skin and subcutaneous tissue disorders
Common:                    Rash*, hyperhidrosis
Uncommon:                  Discolourations other than urine (e.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.
**The incidence rates of myocardial infarction and other ischemic heart disease events (0.43% and 1.54%, respectively) are derived from an analysis of 13 double-blind studies involving 2082 patients with end-of-dose motor fluctuations receiving entacapone.
c. Description of selected adverse reactions
Adverse 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 occuring (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.
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 Stalevo (see section 4.4).
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).
Entacapone in association with levodopa has been associated with isolated cases of excessive daytime somnolence and sudden sleep onset episodes.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il