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Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

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 Reactions Occurring in ≥ 3% of Patients Treated with AMMONUL

Number of patients with any adverse event 163 (52%)
Blood and lymphatic system disorders 35 (11%)
  Anemia 12 (4%)
  Disseminated intravascular coagulation 11 (3%)
Cardiac disorders 28 (9%)
Gastrointestinal disorders 42 (13%)
  Diarrhea 10 (3%)
  Nausea 9 (3%)
  Vomiting 29 (9%)
General disorders and administration-site conditions 45 (14%)
  Injection-site reaction 11 (3%)
  Pyrexia 17 (5%)
Infections 39 (12%)
  Urinary tract infection 9 (3%)
Injury, poisoning and procedural complications 12 (4%)
Investigations 32 (10%)
Metabolism and nutrition disorders 67 (21%)
  Acidosis 8 (3%)
  Hyperammonemia 17 (5%)
  Hyperglycemia 22 (7%)
  Hypocalcemia 8 (3%)
  Hypokalemia 23 (7%)
  Metabolic acidosis 13 (4%)
Nervous system disorders  71 (22%)
  Brain edema 17 (5%)
  Coma 10 (3%)
  Convulsions 19 (6%)
  Mental impairment 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 14 (4%)

Adverse reactions 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 reactions profiles differed 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).

Less common adverse reactions ( < 3% of patients) that are characterized as severe are listed below by body system.

BLOOD AND LYMPHATIC SYSTEM DISORDERS: coagulopathy, pancytopenia, thrombocytopenia

CARDIAC DISORDERS: atrial rupture, bradycardia, cardiac or cardiopulmonary arrest/failure, cardiogenic shock, cardiomyopathy, pericardial effusion

EYE DISORDERS: blindness

GASTROINTESTINAL DISORDERS: abdominal distension, 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


INJURY, POISONING AND PROCEDURAL COMPLICATIONS: brain herniation, subdural hematoma, overdose

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, hypoglycemia, hyperkalemia, hypernatremia, alkalosis, tetany


NERVOUS SYSTEM DISORDERS: areflexia, ataxia, brain infarction, brain hemorrhage, cerebral atrophy, clonus, depressed level of consciousness, encephalopathy, nerve paralysis, intracranial pressure increased, subdural hematoma, 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, blister, pruritis generalized, rash, urticaria

VASCULAR DISORDERS: flushing, hemorrhage, hypertension, phlebothrombosis/thrombosis