RAVICTI

3 Pediatrics 11/2022 TABLE OF CONTENTS Sections or subsections that are not applicable at the time of authorization are not listed . 7

1 Adverse Reaction Overview The incidence of serious adverse events in long term clinical trials with RAVICTI was 26% and consisted primarily of hyperammonemia (18%). The most common adverse drug reactions among all patients taking RAVICTI in clinical trials include diarrhea, flatulence, headache, decreased appetite, vomiting, nausea, fatigue, and skin odor.

Adverse drug reactions that resulted in clinical intervention in UCD patients who participated in clinical trials were mostly gastrointestinal reactions (flatulence, nausea, vomiting, abdominal distention) or neurological reactions (dysgeusia, lethargy, speech disorder, paresthesia, tremor).

2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials, therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse drug reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use. Assessment of adverse drug reactions was based on exposure in 114 UCD patients (65 adults and 49 children between the ages of 2 months and 17 years) across four short term active control studies and three long term (12 month) uncontrolled clinical studies.

Table 2 shows the adverse reactions reported in ≥2% of patients receiving RAVICTI. 1 Clinical Trials Adverse Reactions – Pediatrics Adverse reactions reported in at least 10% of pediatric patients ages 2 years to 17 years were upper abdominal pain, rash, nausea, vomiting, diarrhea, decreased appetite, and headache.

RAVICTI has been evaluated in 17 patients with UCDs ages 2 months to less than 2 years in 3 open-label studies. 2 to 20 months). Adverse reactions reported in at least 10% of pediatric patients aged 2 months to less than 2 years were neutropenia, vomiting, constipation, diarrhea, pyrexia, upper respiratory tract infection, gastroenteritis, otitis media, urinary tract infection, viral infection, hyperammonemia, hypophagia, cough, nasal congestion, rhinorrhea, rash, and papule.

3 Pediatrics 11/2022 TABLE OF CONTENTS Sections or subsections that are not applicable at the time of authorization are not listed . 1 Pregnant Women ..........................................................................................

2 Breast-feeding............................................................................................... 3 Pediatrics ...................................................................................................... 4 Geriatrics ......................................................................................................

3 Less Common Clinical Trial Adverse Reactions .................................................... 4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ........................................................................................................

5 Post-Market Adverse Reactions.......................................................................... 13 9 DRUG INTERACTIONS.................................................................................................. 2 Drug Interactions Overview................................................................................

3 Drug-Behavioural Interactions............................................................................ 4 Drug-Drug Interactions ...................................................................................... 5 Drug-Food Interactions ......................................................................................

6 Drug-Herb Interactions ...................................................................................... 7 Drug-Laboratory Test Interactions ...................................................................... 14 10 CLINICAL PHARMACOLOGY .........................................................................................