Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The expected safety profile for Lecigon is based on available data from clinical trials and post- marketing experience of levodopa/carbidopa intestinal gel and oral levodopa/carbidopa/entacapone.

Drug-related undesirable effects that occur frequently with levodopa/carbidopa intestinal gel and could therefore occur with Lecigon include nausea and dyskinesia. Device and procedure-related undesirable effects that occur frequently with levodopa/carbidopa intestinal gel and could therefore occur with Lecigon include abdominal pain, complications of tube insertion, excessive granulation tissue, incision site erythema, postoperative wound infection, post-procedural discharge, procedure-related pain, and incision 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.

The most commonly reported adverse reactions with oral levodopa/carbidopa/entacapone are dyskinesias (affecting approximately 19% of patients); gastrointestinal symptoms including nausea and diarrhoea (affecting approximately 15% and 12% of patients respectively); muscle and connective tissue disorders (affecting approximately 12% of patients); and harmless maroon discolouration of urine (chromaturia) (affecting approximately 10% of patients). Serious adverse reactions for gastrointestinal haemorrhage (uncommon) and angioedema (rare) have been identified from clinical trials with oral levodopa/carbidopa/entacapone or entacapone in combination with levodopa/DDC inhibitor.
Serious hepatitis with mainly cholestatic elements, rhabdomyolysis and neuroleptic malignant syndrome may occur with oral levodopa/carbidopa/entacapone, although no case has been identified from clinical trials.

A pharmacokinetic study with Lecigon that included 11 patients with advanced Parkinson's disease was performed. Adverse reactions considered to be associated with Lecigon were headache, nausea and dizziness. No serious adverse reactions were reported in this 2-day study. No adverse reactions were considered to be associated with the pump during administration of Lecigon.
Table of adverse reactions
Adverse reactions related to the medicinal product, device and procedure-related adverse reactions observed in clinical trials and during post-marketing use of levodopa/carbidopa intestinal gel and oral levodopa/carbidopa/entacapone are summarised in Table 1 below by system organ class and frequency.

For oral levodopa/carbidopa/entacapone, the adverse reactions listed in Table 1 have been compiled from double-blind clinical trials and data collected during post-marketing use of entacapone for combination therapy with levodopa/DDC inhibitor.

Table 1.          Adverse reactions from clinical trials and post-marketing experience of levodopa/carbidopa intestinal gel and/or oral levodopa/carbidopa/entacapone.
MedDRA           Very            Common            Uncommon            Rare          Frequency not system organ     common          (≥1/100 to        (≥1/1000 to         (≥1/10,000    known (cannot class            (≥1/10)         <1/10)            <1/100)             to <1/1000)   be estimated from available data)
Drug-related adverse reactions
Infections and   Urinary tract infestations     infection
Blood and                        Anaemia           Leukopenia,                       Agranulocytosis lymphatic                                          Thrombocytope system                                             nia disorders
Immune                                                                               Anaphylactic system                                                                               reaction disorders
Metabolism       Weight loss     Elevated amino and nutrition                    acid level disorders                        (elevated methylmalonic acid),
Elevated homocysteine in the blood,
Decreased appetite,
Weight gain,
Vitamin B6 deficiency,
Vitamin B12 deficiency
Psychiatric      Anxiety,        Nightmares,       Completed           Abnormal      Dopamine disorders        Depression,     Agitation,        suicide,            thoughts      dysregulation Insomnia        Confused state,   Disorientation,                   syndromea Hallucination,    Euphoria,
Impulse control   Fear,
disorder,         Increased libido
Psychotic         (see section 4.4) disorders,        Suicide attempt/
Sleep attacks,    suicidal
Sleep disorder    behaviour
MedDRA           Very            Common             Uncommon             Rare            Frequency not system organ     common          (≥1/100 to         (≥1/1000 to          (≥1/10,000      known (cannot class            (≥1/10)         <1/10)             <1/100)              to <1/1000)     be estimated from available data)
Nervous          Dyskinesia,     Dizziness,         Ataxia,                              Neuroleptic system           Parkinson's     Dystonia,          Convulsions                          malignant disorders        disease/        Headache,                                               syndrome, Exacerbation    Hypoaesthesia,                                          Memory of              On-off                                                  impairment, parkinsonism    phenomenon,                                             Dementia (e.g.           Paraesthesia,
bradykinesia)   Polyneuropathy,
Somnolence,
Syncope,
Tremor,
Hyperkinesia
Eye disorders                    Blurred vision     Angle closure glaucoma,
Blepharospasm,
Diplopia,
Optic ischaemic neuropathy
Cardiac                          Irregular heart    Palpitations,
disorders                        rate,              Myocardial
Ischaemic heart    infarction disease other than myocardial infarction (e.g.
angina pectoris)
Vascular         Orthostatic     Hypertension,      Phlebitis disorders        hypotension     Hypotension
Respiratory,                     Dyspnoea,          Dysphonia            Abnormal thoracic and                     Oropharyngeal                           breathing mediastinal                      pain,                                   pattern disorders                        Aspiration pneumonia
Gastrointestin   Nausea,         Abdominal          Colitis,             Bruxism, al disorders     Constipation,   distension,        Gastrointestinal     Glossodynia, Diarrhoea       Abdominal          haemorrhage,         Hiccups,
pain,              Hypersalivation      Saliva
Abdominal                               discolouratio discomfort,                             n
Dry mouth,
Dysgeusia,
Dyspepsia,
Dysphagia,
Flatulence,
Vomiting
Hepatobiliary                                       Abnormal liver                       Hepatitis with disorders                                           function test                        mainly cholestatic elements
Skin and                         Contact            Alopecia,            Malignant subcutaneous                     dermatitis,        Erythema,            melanoma tissue                           Hyperhidrosis,     Urticaria,           (see section disorders                        Pruritus,          Discolouration       4.3) Skin rash          of the skin, hair,   Angioedema nails and sweat
MedDRA            Very            Common            Uncommon          Rare          Frequency not system organ      common          (≥1/100 to        (≥1/1000 to       (≥1/10,000    known (cannot class             (≥1/10)         <1/10)            <1/100)           to <1/1000)   be estimated from available data)
Musculoskelet     Pain in         Arthralgia,                                       Rhabdomyolysis al and            muscles and     Muscle spasms,
connective        tissues, and    Neck pain tissue            musculoskelet disorders         al pain
Renal and         Chromaturia     Urinary urinary                           incontinence,
disorders                         Urinary retention,
Reproductive                                                          Priapism system and breast disorders
General                           Asthenia,         Malaise disorders and                     Chest pain,
administration                    Fatigue,
site conditions                   Gait disturbance,
Pain,
Peripheral oedema
Injury,           Fall poisoning and procedural complications
Device and procedure-related adverse reactions
Infections and    Postoperative    Incision site    Postoperative                   Sepsis infestations      wound            cellulitis,      abscess infection        Post-procedural infection
Gastrointestin    Abdominal        Abdominal        Bezoar,                         Gastric al disorders      pain             discomfort,      Ischaemic                       perforation, Upper            colitis,                        Gastrointestinal abdominal pain, Gastrointestinal                 perforation,
Peritonitis,     ischaemia,                      Small intestinal
Pneumoperitone Gastrointestinal                  ischaemia,
um               obstruction,                    Small intestinal
Pancreatitis,                   perforation
Small intestinal haemorrhage,
Small intestinal ulcer,
Large intestine perforation,
Intussusception
Skin and          Excessive subcutaneous      granulation tissue            tissue disorders
General           Complications   Device disorders and     of device       dislocation,
administration    insertionb      Device site conditions                   occlusion
MedDRA          Very              Common             Uncommon      Rare          Frequency not system organ    common            (≥1/100 to         (≥1/1000 to   (≥1/10,000    known (cannot class           (≥1/10)           <1/10)             <1/100)       to <1/1000)   be estimated from available data)
Injury,         Incision site     Gastrointestinal poisoning and   erythema,         stoma procedural      Post-             complication,
complications   procedural        Incision site discharge,        pain,
Procedural        Postoperative pain,             ileus,
Procedural site   Post-procedural reaction          complication,
Post-procedural discomfort,
Post-procedural haemorrhage a
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 section 4.4).
b
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 one or more of the following adverse reactions for the nasojejunal tube: oropharyngeal pain, abdominal distension, abdominal pain, abdominal discomfort, pain, throat irritation, gastrointestinal injury, oesophageal haemorrhage, anxiety, dysphagia, and vomiting. For the PEG-J, this adverse reaction was co-reported with one or more of the following adverse reactions: abdominal pain, abdominal discomfort, abdominal distension, flatulence, or pneumoperitoneum. Other adverse reactions that were co-reported with complication of device insertion included abdominal discomfort, duodenal ulcer, haemorrhage, erosive duodenitis, erosive gastritis, gastrointestinal haemorrhage, peritonitis, pneumoperitoneum, and small intestine ulcer.


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

The following additional adverse reactions have been observed with oral levodopa/carbidopa and have been classified as rare (≤1/10,000 to <1/1000): haemolytic anaemia, trismus, Horner's syndrome, mydriasis, oculogyric crises, and Henoch-Schönlein purpura. The following additional adverse reaction has been reported as very rare (<1/10,000): agranulocytosis

Laboratory values:
The following laboratory abnormalities have been reported with levodopa/carbidopa treatment: elevated urea nitrogen, alkaline phosphatases, S-AST, S-ALT, LDH, bilirubin, blood sugar, creatinine, uric acid, positive Coomb's test, and lowered haemoglobin and haematocrit levels. Leucocytes, bacteria and blood in the urine have been reported.

Description of selected adverse reactions
The introduction of entacapone to an existing treatment with levodopa/DDC inhibitor may cause an initial increase in dopaminergic activity (e.g. dyskinesia, nausea and vomiting). Reducing the levodopa dose reduces the severity and frequency of these dopaminergic reactions.

Impulse control disorders
Compulsive 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 therapies containing levodopa, including Lecigon (see section 4.4).
Somnolence and sudden sleep attacks
Entacapone in combination with levodopa has been associated with somnolence and sudden sleep attacks in patients with Parkinson's disease. Caution should therefore be exercised when driving and using machines (see sections 4.4 and 4.7).

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 http://sideeffects.health.org.co.il