ADVERSE REACTIONS
The safety data were obtained from 316 patients who received AMMONUL® as emergency (rescue) or prospective treatment for hyperammonemia as part of an uncontrolled, open-label study. The study population included patients between the ages of 0 to 53 years with a mean (SD) of 6.2 (8.54) years; 51% were male and 49% were female who had the following diagnoses: OTC (46%), ASS (22%), CPS (12%), ASL (2%), ARG (< 1%), THN (< 1%), and other (18%).
Table 2 Adverse Events Occurring in ≥ 3% of Patients Treated with AMMONUL® | Patients
N=316 |
|---|
| No. patients with any adverse event | 163 (52%) |
| Blood and lymphatic system disorders | 35 (11%) |
| Anemia NOS | 12 (4%) |
| Disseminated intravascular coagulation | 11 (3%) |
| Cardiac disorders | 28 (9%) |
| Gastrointestinal disorders | 42 (13%) |
| Diarrhea NOS | 10 (3%) |
| Nausea | 9 (3%) |
| Vomiting NOS | 29 (9%) |
| General disorders and administration-site conditions | 45 (14%) |
| Injection-site reaction NOS | 11 (3%) |
| Pyrexia | 17 (5%) |
| Infections | 39 (12%) |
| Urinary tract infection NOS | 9 (3%) |
| Injury, poisoning and procedural complications | 12 (4%) |
| Investigations | 32 (10%) |
| Metabolism and nutrition disorders | 67 (21%) |
| Acidosis NOS | 8 (3%) |
| Hyperammonemia | 17 (5%) |
| Hyperglycemia NOS | 22 (7%) |
| Hypocalcemia | 8 (3%) |
| Hypokalemia | 23 (7%) |
| Metabolic acidosis NOS | 13 (4%) |
| Nervous system disorders | 71 (22%) |
| Brain edema | 17 (5%) |
| Coma | 10 (3%) |
| Convulsions NOS | 19 (6%) |
| Mental impairment NOS | 18 (6%) |
| Psychiatric disorders | 16 (5%) |
| Agitation | 8 (3%) |
| Renal and urinary disorders | 14 (4%) |
| Respiratory, thoracic and mediastinal disorders | 47 (15%) |
| Respiratory distress | 9 (3%) |
| Skin and subcutaneous tissue disorders | 19 (6%) |
| Vascular disorders | 19 (6%) |
| Hypotension NOS | 14 (4%) |
Clinically Important Adverse Reactions
Adverse events occurred most frequently in the following system organ classes: nervous system disorders (22% of patients), metabolism and nutrition disorders (21% of patients), and respiratory, thoracic and mediastinal disorders (15% of patients). The most frequently reported adverse events were vomiting (9% of patients), hyperglycemia (7% of patients), hypokalemia (7% of patients), convulsions (6% of patients), and mental impairment (6% of patients).
Adverse events leading to study drug discontinuation occurred in 4% of patients. Metabolic acidosis and injection-site reactions each led to discontinuation in 2 patients (< 1%). Adverse events leading to discontinuation in 1 patient included bradycardia, abdominal distension, injection-site extravasation, injection-site hemorrhage, blister, overdose, subdural hematoma, hyperammonemia, hypoglycemia, clonus, coma, increased intercranial pressure, hypercapnia, Kussmaul respiration, respiratory distress, respiratory failure, pruritis, and maculo-papular rash.
Subpopulation and Risk Factor Data
Adverse events were reported with similar frequency in patients with OTC, ASS, CPS, and diagnoses categorized as "other." Nervous system disorders were more frequent in patients with OTC and CPS, compared with patients with ASS and patients with "other" diagnoses. Convulsions and mental impairment were reported in patients with OTC and CPS. These observations are consistent with literature reports that patients with enzyme deficiencies occurring earlier in the urea cycle (i.e., OTC and CPS) tend to be more severely affected.
Adverse event profiles did differ by age group. Patients ≤ 30 days of age had more blood and lymphatic system disorders and vascular disorders (specifically hypotension), while patients > 30 days of age had more gastrointestinal disorders (specifically nausea, vomiting and diarrhea).
Other Less Common Adverse Events Occurring in < 3% of Patients
Less common adverse events that could represent drug-induced reactions or are characterized as severe are listed below by body system.
BLOOD AND LYMPHATIC SYSTEM DISORDERS: coagulopathy, pancytopenia, thrombocytopenia
CARDIAC DISORDERS: atrial rupture, cardiac or cardiopulmonary arrest/failure, cardiogenic shock, cardiomyopathy, pericardial effusion
EYE DISORDERS: blindness
GASTROINTESTINAL DISORDERS: gastrointestinal hemorrhage
GENERAL DISORDERS AND ADMINISTRATION-SITE CONDITIONS: asthenia, brain death, chest pain, multiorgan failure, edema
HEPATOBILIARY DISORDERS: cholestasis, hepatic artery stenosis, hepatic failure/ hepatotoxicity, jaundice
INFECTIONS AND INFESTATIONS: sepsis/septic shock
INJURY, POISONING AND PROCEDURAL COMPLICATIONS: brain herniation, subdural hematoma
INVESTIGATIONS: blood carbon dioxide changes, blood glucose changes, blood pH increased, cardiac output decreased, pCO2 changes, respiratory rate increased
METABOLISM AND NUTRITION DISORDERS: alkalosis, dehydration, fluid overload/retention, hyperkalemia, hypernatremia, alkalosis, tetany
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED: hemangioma acquired
NERVOUS SYSTEM DISORDERS: areflexia, ataxia, brain infarction, brain hemorrhage, cerebral atrophy, clonus, depressed level of consciousness, encephalopathy, nerve paralysis, intracranial pressure increased, tremor
PSYCHIATRIC DISORDERS: acute psychosis, aggression, confusional state, hallucinations
RENAL AND URINARY DISORDERS: anuria, renal failure, urinary retention
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: acute respiratory distress syndrome, dyspnea, hypercapnia, hyperventilation, Kussmaul respiration, pneumonia aspiration, pneumothorax, pulmonary hemorrhage, pulmonary edema, respiratory acidosis or alkalosis, respiratory arrest/failure
SKIN AND SUBCUTANEOUS TISSUE DISORDERS: alopecia, pruritis generalized, rash, urticaria
VASCULAR DISORDERS: flushing, hemorrhage, hypertension, phlebothrombosis/thrombosis
|
