Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Drug-related undesirable effects that occur frequently with the Duodopa system include nausea and dyskinesia.
Device- and procedure related undesirable effects that occur frequently with the Duodopa system include abdominal pain, complications of device insertion, excessive granulation tissue, incision site erythema, postoperative wound infection, post procedural discharge, procedural pain, and procedural site reaction.

Most of these adverse reactions were reported early in the studies, subsequent to the percutaneous endoscopic gastrostomy procedure and occurred during the first 28 days.

Undesirable effects reported with Duodopa
The safety of Duodopa was compared to the standard oral formulation of levodopa/carbidopa (100 mg/25 mg) in a total of 71 advanced Parkinson's disease patients who participated in a randomized, double-blind, double-dummy, active controlled study of 12 weeks duration.
Additional safety information was collected in an open-label, 12-month study in 354 patients with advanced Parkinson's disease and open-label extension studies.

An analysis was performed for patients who received Duodopa in all studies, regardless of the study design (double-blind or open-label) to allow for a summary of drug-related adverse reactions. Another analysis was performed for patients who received Duodopa or placebo gel through a PEG-J to allow for a summary of procedure-related and device-related adverse reactions in all studies, regardless of the study design (double-blind or open-label).

Drug-, Procedure- and device-related adverse reactions based on treatment emergent frequencies, regardless of causality assigned, in addition to adverse reactions identified during post-approval use of Duodopa are presented in Table 1.



Table 1. Adverse Reaction Data Derived From Clinical Trials and Post-marketing Experience 
MedDRA          Very Commona           Commona             Uncommonb            Rareb          Frequency System Organ         (≥ 1/10)           (≥ 1/100 to <        (>1/1,000 to     (>1/10,000 to      Unknown Class                                   1/10)              <1/100)          <1/1,000)           Post- marketing

Drug-Related Adverse Reactions

Infections and    Urinary tract infestations      infections

Blood and                             Anaemia               Leukopenia, lymphatic                                                   Thrombo- system                                                      cytopenia disorders
Immune                                                                                          Anaphylactic System                                                                                          reaction Disorders
Metabolism        Weight              Increased and nutrition     decreased           weight,
disorders                             Amino acid level increased
(Metylmalonic acid increased),
Blood homocysteine
increased,
Decreased appetite,
Vitamin B6 deficiency,
Vitamin B12 deficiency

Psychiatric     Anxiety,       Abnormal             Completed          Abnormal          Dopamine disorders       Depression,    dreams,              suicide,           thinking          dysregulation Insomnia       Agitation,           Dementia,                            syndromed Disorientation,
Confusional          Euphoric mood,
state,               Fear,

Hallucination,       Libido increased
Impulsive            (See Section behaviorc,           4.4),
Psychotic            Nightmare,
disorder,            Suicide Attempt
Sleep attacks,
Sleep disorder
Nervous         Dyskinesia,    Dizziness,           Ataxia,
system          Parkinson’s    Dystonia,            Convulsion,
disorders       disease        Headache,            Gait disturbance
Hypoaesthesia,
On and off phenomenon,
Paraesthesia,

Polyneuropathy,
Somnolence,
Syncope,
Tremor
Eye disorders                                       Angle closure glaucoma,
Blepharospasm,
Diplopia,
Optic ischaemic neuropathy,
Vision blurred
Cardiac                        Heart rate           Palpitations disorders                      irregular
Vascular        Orthostatic    Hypertension,        Phlebitis disorders       hypotension    Hypotension
Respiratory,                   Dyspnoea,            Chest pain,        Respiration thoracic and                   Oropharyngeal        Dysphonia          abnormal mediastinal                    pain disorders
Gastro-         Nausea,        Abdominal            Salivary           Bruxism, intestinal      Constipation   distension,          hypersecretion     Saliva disorders                      Diarrhoea,                              discolouration, Dry mouth,                              Glossodynia,
Dysgeusia,                              Hiccups
Dyspepsia,
Dysphagia,
Flatulence,
Vomiting


Skin and                             Dermatitis           Alopecia,          Sweat subcutaneous                         contact,             Erythema,          discolouration, tissue disorders                     Hyperhidrosis,       Urticaria          Malignant Oedema                                  melanoma peripheral,                             (See Section
Pruritus,                               4.4)
Rash
Musculoskeleta                       Muscle spasms,
l and                                Neck pain connective tissue disorders
Renal and                            Urinary              Chromaturia        Priapism urinary                              incontinence,
disorders                            Urinary retention
General                              Fatigue,             Malaise disorders and                        Pain,
administration                       Asthenia site conditions
Injury,            Fall poisoning and procedural complications
Device- and Procedure-Related Adverse Reactions

MedDRA             Very Commona        Commona             Uncommonb             Rareb          Frequency System Organ          (≥ 1/10)        (≥ 1/100 to <        (>1/1,000 to      (>1/10,000 to      Unknown Class                                     1/10)              <1/100)         <1/1,000)             Post- marketing

Infections and     Postoperative     Incision site        Postoperative                        Sepsis infestations       wound infection   cellulitis,          abscess
Post procedural infection
Gastro-            Abdominal pain    Abdominal            Bezoar (see                          Gastric intestinal                           discomfort,          section 4.4),                        perforation, disorders                            Abdominal pain       Colitis                              Gastro- upper,               ischaemic,                           intestinal
Peritonitis,         Gastrointestinal                     perforation, Pneumo-              ischaemia,                           Small peritoneum           Gastrointestinal                     intestinal obstruction,                         ischaemia,
Intussusception,                     Small
Pancreatitis,                        intestinal
Small intestinal                     perforation haemorrhage,
Small intestinal ulcer,
Large intestine perforation
Respiratory,                         Pneumonia / thoracic and                         Aspiration mediastinal                          pneumonia
disorders


Skin and            Excessive subcutaneous        granulation tissue disorders    tissue
General             Complications of      Device disorders and       device                dislocation,
administration      insertione            Device site conditions                           occlusion

Injury,             Incision site         Gastrointestinal poisoning and       erythema,             stoma procedural          Post procedural       complication,
complications       discharge,            Incision site
Procedural pain,      pain,
Procedural site       Postoperative reaction              Ileus,
Post procedural complication,
Post procedural discomfort,
Post procedural haemorrhage
 a ADRs observed in clinical trials. Frequencies assigned reflect adverse event frequencies and are regardless of  causality assigned by the investigator b ADRs observed with Duodopa for which estimations of frequencies were not available. Frequencies assigned are  based on historical data for oral levodopa/carbidopa.
c Impulse control disorders: Pathological gambling, increased libido and 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 Duodopa (see section 4.4. ‘Special warnings and precautions for use’).
d Dopamine Dysregulation Syndrome (DDS) is an addictive disorder seen in some patients treated with levodopa/  carbidopa. 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).
e Complication of device insertion was a commonly reported adverse reaction for both the nasojejunal tube and the 
PEG-J. This adverse reaction was co-reported with 1 or more of the following adverse reactions for the nasojejunal tube: oropharyngeal pain, abdominal distention, abdominal pain, abdominal discomfort, pain, throat irritation, gastrointestinal injury, esophageal haemorrhage, anxiety, dysphagia, and vomiting. For the PEG-J, this adverse reaction was co-reported with 1 or more of the following adverse reactions: abdominal pain, abdominal discomfort, abdominal distension, flatulence, or pneumoperitoneum. Other non-serious adverse reactions that were co-reported with complication of device insertion included abdominal discomfort, abdominal pain upper, duodenal ulcer, duodenal ulcer haemorrhage, erosive duodenitis, gastritis erosive, gastrointestinal haemorrhage, peritonitis, pneumoperitoneum, small intestine ulcer.

Dislocation of the intestinal tube backwards into the stomach or an obstruction in the device leads to reappearance of the motor fluctuations.


The following additional adverse reactions (listed in MedDRA preferred terms) have been observed with oral levodopa/carbidopa and could occur with Duodopa:

Table 2.   Adverse Reaction Observed with Oral Levodopa/Carbidopa

MedDRA system organ                       Rare                           Very Rare class                      (≥1/10,000 to <1/1,000)                (<1/10,000) 
Blood and lymphatic system      Haemolytic anaemia               Agranulocytosis disorders
Nervous system disorders        Trismus,
Neuroleptic malignant syndrome (see Section 4.4)
Eye disorders                   Horner’s syndrome,
Mydriasis,
Oculogyric crises
Skin and subcutaneous tissue    Angiooedema,
disorders                       Henoch-Schönlein purpura


Laboratory values: The following laboratory abnormalities have been reported with levodopa/carbidopa treatment and should, therefore, be acknowledged when treating patients with Duodopa: 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 Duodopa, 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