Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile

Assessment of adverse reactions was based on exposure in 114 UCD patients (65 adults and 49 children between the ages of 2 months and 17 years) with deficiencies in CPS, OTC, ASS, ASL, ARG, or HHH across 4 short term and 3 long term clinical studies, in which 90 patients completed 12 months duration (median exposure = 51 weeks).

At the beginning of the treatment, abdominal pain, nausea, diarrhoea, and/or headache may occur; these reactions usually disappear within a few days even if treatment is continued. The most frequently reported adverse reactions (>5%) during glycerol phenylbutyrate treatment were diarrhoea, flatulence, and headache (8.8% each); decreased appetite (7.0%), vomiting (6.1%); and fatigue, nausea and, skin odour abnormal (5.3% each).

Additional adverse reactions have been evaluated in a clinical study including 16 UCD patients less than 2 months of age. The median exposure was 10 months (range 2 to 20 months).


Tabulated list of adverse reactions
The adverse reactions are listed below, by system organ class and by frequency. Frequency is defined as 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Any adverse reaction reported in one patient met the uncommon criteria. Due to the rarity of the UCD population, and the small size of the medicinal product safety population database (N=114), the adverse reaction frequency for rare and very rare is not known.

Table 1. List of adverse reactions
System organ class                     Frequency                        Adverse reaction Infections and infestations            Uncommon            Gastrointestinal viral infection Endocrine disorders                    Uncommon            Hypothyroidism Metabolism and nutrition                Common             Decreased appetite, increased appetite disorders                              Uncommon            Hypoalbuminaemia, hypokalaemia Psychiatric disorders                   Common             Food aversion Nervous system disorders                Common             Dizziness, headache, tremor Uncommon            Dysgeusia, lethargy, paraesthesia,
psychomotor hyperactivity, somnolence,
speech disorder
Uncommon            Confusional state, depressed mood
Cardiac disorders                      Uncommon            Ventricular arrhythmia Vascular disorders                     Uncommon            Hot flush
Respiratory, thoracic and              Uncommon            Dysphonia, epistaxis, nasal congestion, Ravicti-SPC-0423-V1
mediastinal disorder                                        oropharyngeal pain, throat irritation Gastrointestinal disorders                Common            Flatulence, diarrhoea, vomiting, nausea, abdominal pain, dyspepsia, abdominal distension, constipation, oral discomfort,
retching
Uncommon            Abdominal discomfort, abnormal faeces,
dry mouth, eructation, defaecation urgency, upper abdominal pain and/or lower abdominal pain, painful defaecation,
steatorrhoea, stomatitis
Hepatobiliary disorders                 Uncommon            Gallbladder pain Skin and subcutaneous tissue             Common             Abnormal skin odour, acne disorders                               Uncommon            Alopecia, hyperhidrosis, pruritic rash Musculoskeletal and connective                              Back pain, joint swelling, muscle spasm, Uncommon tissue disorders                                            pain in extremity, plantar fasciitis Renal and urinary disorders             Uncommon            Bladder pain Reproductive system and breast           Common             Metrorrhagia disorders                               Uncommon            Amenorrhoea, irregular menstruation General disorders and                    Common             Fatigue, oedema peripheral administration site conditions          Uncommon            Hunger, pyrexia Investigations                           Common             Increased aspartate aminotransferase, alanine aminotransferase increased,
increased anion gap, decreased lymphocyte count, decreased vitamin D
Uncommon            Blood potassium increased, blood triglycerides increased, electrocardiogram abnormal, low density lipoprotein increased, prothrombin time prolonged,
white blood cell count increased, weight increased, weight decreased


Paediatric population
Adverse reactions reported in more paediatric than adult patients during long-term treatment with glycerol phenylbutyrate included upper abdominal pain (3 of 49 paediatric [6.1%] versus 1 of 51 adults [2.0%] and increased anion gap (2 of 49 paediatric [4.1%] versus 0 of 51 adults [0%].

In an additional long term (24 month), uncontrolled, open-label clinical study the safety of RAVICTI has been evaluated in 16 UCD patients less than 2 months of age and 10 paediatric patients with UCDs aged 2 months to less than 2 years. The median exposure was 10 months (range 2 to 20 months) and median exposure in the 2 months to less than 2 years of age was 9 months (range 0.2 to 20.3 months).
Adverse reactions are summarized below.


Table 2. List of adverse reactions in patients less than 2 months of age System organ class                                                            Total Preferred Term                                                          (N=16) Blood and lymphatic system disorders                                       2 (12.5%) Anaemia                                                                1 (6.3%) Ravicti-SPC-0423-V1
Thrombocytosis                                                         1 (6.3%) Metabolism and nutrition disorders                                     1 (6.3%) Hypophagia                                                             1 (6.3%) Gastrointestinal disorders                                                  3 (18.8%) Diarrhoea,                                                            2 (12.5%) Constipation                                                           1 (6.3%) Flatulence                                                             1 (6.3%) Gastrooesophageal reflux disease                                       1 (6.3%) Skin and subcutaneous tissue disorders                                3(18.8%) Rash                                                                  3(18.8%) Investigations                                                               4 (25%) Amino acid level decreased                                             1 (6.3%) Gamma-glutamyltransferase increased                                    1 (6.3%) Hepatic enzyme increased                                               1 (6.3%) Transaminases increased                                                1 (6.3%) 

Table 3. List of adverse reactions in patients 2 months to less than 2 years of age System Organ Class                                                              Total Preferred Term                                                           (N=10) Gastrointestinal disorders                                                    2 (20%) Constipation                                                             1 (10%) Diarrhoea                                                                1 (10%) Skin and subcutaneous tissue disorders                                        2 (20%) Eczema                                                                   1 (10%) Nail ridging                                                             1 (10%) Rash                                                                     1 (10%) 


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/