Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The most frequent adverse reactions (≥10%) reported in all Phase 3 studies in patients exposed to Produodopa were infusion site events (infusion site erythema, infusion site cellulitis, infusion site nodule, infusion site pain, infusion site oedema, infusion site reaction, and infusion site infection), hallucination, fall, and anxiety.

Tabulated list of adverse reactions

Adverse reactions reported in all Phase 3 studies in patients exposed to Produodopa (379 patients with total exposure of 414.3 person-years, 230 subjects exposed for ≥ 6 months, 204 subjects exposed for ≥ 12 months) or data from Duodopa Intestinal Gel based on treatment emergent frequencies, regardless of causality assigned are presented in Table 5, listed by MedDRA system organ class.
Adverse reaction frequencies are based on 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); and very rare (<1/10 000).

Table 5. List of adverse reactions



System organ class              Frequency         Adverse reactions
Infections and infestations   Very common         Infusion site cellulitis Infusion site infection
Urinary tract infectionb
Commona             Infusion site abscess
Blood and lymphatic system    Common              Anaemiab disorders                     Uncommon            Leukopeniab
Thrombocytopeniab
Immune system disorders       Not known           Anaphylactic reactionb,e Metabolism and nutrition      Common              Decreased appetite disorders
Psychiatric disorders         Very common         Anxiety
Depression
Hallucinationc
Common              Abnormal dreamsb
Agitationb
Confusional state
Delusion
Impulse control disorder
Insomnia
Paranoia
Psychotic disorder
Sleep attacksb
Sleep disorderb
Suicidal ideation
Uncommon            Completed suicideb
Dementiab
Disorientationb
Dopamine dysregulation syndrome
Euphoric moodb
Fearb
Libido increasedb
Nightmareb
Suicide attemptb
Rare                Abnormal thinkingb
Nervous system disorders      Common              Cognitive disorder
Dizziness
Dizziness postural
Dyskinesia
Dystonia
Headache
Hypoaesthesia
On and off phenomenon
Paraesthesia
Polyneuropathyd
Somnolence
Syncope
Tremorb
Uncommon            Ataxiab
Convulsionb
Gait disturbanceb


Eye disorders                    Uncommon           Angle closure glaucomab Blepharospasmb
Diplopiab
Optic ischaemic neuropathyb
Vision blurredb
Cardiac disorders                Common             Heart rate irregularb Uncommon           Palpitations
Vascular disorders               Common             Hypertension
Hypotension
Orthostatic hypotension
Uncommon           Phlebitisb
Respiratory, thoracic and        Common             Dyspnoea mediastinal disorders                               Oropharyngeal painb Uncommon           Dysphoniab
Rare               Respiration abnormalb
Gastrointestinal disorders       Common             Abdominal distensionb Abdominal pain
Constipation
Diarrhoea
Dry mouth
Dysgeusiab
Dyspepsiab
Dysphagiab
Flatulenceb
Nausea
Vomiting
Uncommon           Salivary hypersecretionb
Rare               Bruxismb
Saliva discolourationb
Glossodyniab
Hiccupsb
Skin and subcutaneous tissue     Common             Dermatitis contactb disorders                                           Hyperhidrosisb
Pruritus
Rash
Uncommon           Alopeciab
Erythemab
Urticariab
Rare               Sweat discolourationb
Malignant melanomab
Musculoskeletal and              Common             Muscle spasms connective tissue disorders                         Neck painb
Renal and urinary disorders      Common             Urinary incontinence Urinary retention
Uncommon           Chromaturiab
Rare               Priapismb
General disorders and            Very common        Infusion site erythema administration site conditions                      Infusion site reaction Infusion site nodule
Infusion site oedema
Infusion site pain



Commona                            Asthenia
Fatigue
Infusion site bruising
Infusion site exfoliation
Infusion site extravasation
Infusion site haematoma
Infusion site haemorrhage
Infusion site induration
Infusion site inflammation
Infusion site irritation
Infusion site mass
Infusion site papule
Infusion site pruritus
Infusion site rash
Infusion site swelling
Malaise
Oedema peripheral
Painb
Uncommon                           Chest painb
Investigations                     Common                             Amino acid level increased (Methylmalonic acid increased)b
Blood homocysteine level increasedb
Vitamin B6 decreased
Vitamin B12 deficiencyb
Weight decreased
Weight increasedb
Injury, poisoning and                Very common                      Fall procedural complications a
Common adverse reactions pertaining to infusion site events included if ≥2%.
b
These adverse reactions were identified with Duodopa Intestinal Gel as drug-related events.
However, these events were not considered adverse reactions for Produodopa.
c
Hallucination includes hallucination, hallucination visual, hallucination auditory, hallucination olfactory, hallucinations tactile, and hallucinations mixed.
d
Polyneuropathy includes neuropathy peripheral, polyneuropathy, decreased vibratory sense, peripheral sensory neuropathy, sensory disturbance, and sensory loss.
e
Based on post-marketing data

Description of selected adverse reactions

Infusion site events
In the Phase 3 studies, the most common AEs related to Produodopa were infusion site reactions 77.6% (N=294) and infusion site infections 41.4% (N=157). Infusion site events including infusion site reactions and infections, commonly seen with subcutaneous infusions were observed with Produodopa in the clinical studies. The majority of the infusion site events were non-serious, were mild or moderate in severity, and resolved spontaneously or with treatment such as antibiotics and/or incision and drainage. Three subjects with infusion site infections had a complication of sepsis resulting in hospitalisation. Monitor for any skin changes at the infusion site that could indicate a potential infection, such as redness associated with warmth, swelling, pain, and discolouration when you apply pressure to it. Aseptic techniques should be followed while using this medication and consider rotating the infusion site more frequently than every 3rd day, using a new infusion set if you 

see these skin changes. It is recommended that new infusion sites be at least 2.5 cm from sites used within the previous 12 days.

Laboratory values: The following laboratory abnormalities have been reported with levodopa/carbidopa treatment and should, therefore, be acknowledged when treating patients with Produodopa: elevated urea nitrogen, alkaline phosphatases, S-AST, S-ALT, LDH, bilirubin, blood sugar, creatinine, uric acid and positive Coomb’s test, and lowered values of haemoglobin and haematocrit. Leucocytes, bacteria and blood in the urine have been reported. Levodopa/carbidopa, and thus Produodopa, may cause a false positive result when a dipstick is used to test for urinary ketone; this reaction is not altered by boiling the urine sample. The use of glucose oxidase methods may give false negative results for glucosuria.


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