Ammonul (Page 2 of 5)

3 DOSAGE FORMS AND STRENGTHS

AMMONUL (sodium phenylacetate and sodium benzoate) Injection 10% per 10% is a sterile, concentrated, aqueous solution of sodium phenylacetate and sodium benzoate.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Decreased Potassium Levels

Because urine potassium loss is enhanced by the excretion of the non-reabsorbable anions, phenylacetylglutamine and hippurate, plasma potassium levels should be carefully monitored and appropriate treatment given when necessary.

5.2 Conditions Associated with Fluid Overload

AMMONUL contains 30.5 mg of sodium per mL of undiluted product. Thus, AMMONUL should be used with great care, if at all, in patients with congestive heart failure or severe renal insufficiency, and in clinical states in which there is sodium retention with edema. Discontinue administration of AMMONUL, evaluate the patient, and institute appropriate therapeutic countermeasures if an adverse event occurs.

5.3 Extravasation

Administration must be through a central venous catheter. Administration through a peripheral line may cause burns. Bolus infusion flow rates are relatively high, especially for infants [see Dosage and Administration (2)]. Extravasation of AMMONUL into the perivenous tissues may lead to skin necrosis. If extravasation is suspected, discontinue the infusion and resume at a different infusion site, if necessary. The infusion site must be monitored closely for possible infiltration during drug administration. Do not administer undiluted product.

5.4 Neurotoxicity of Phenylacetate

Because of prolonged plasma levels achieved by phenylacetate in pharmacokinetic studies, repeat loading doses of AMMONUL should not be administered. Additionally, neurotoxicity was reported in cancer patients receiving intravenous phenylacetate, 250–300 mg/kg/day for 14 days, repeated at 4-week intervals. Manifestations were predominantly somnolence, fatigue, and lightheadedness, with less frequent headaches, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation of a pre-existing neuropathy. The acute onset of symptoms upon initiation of treatment and reversibility of symptoms when the phenylacetate was discontinued suggest a drug effect [see Animal Toxicology and/or Pharmacology (13.2)].

5.5 Hyperventilation and Metabolic Acidosis

Due to structural similarities between phenylacetate and benzoate to salicylate, AMMONUL may cause side effects typically associated with salicylate overdose, such as hyperventilation and metabolic acidosis. Monitoring of blood chemistry profiles, blood pH and pCO2 should be performed.

6 ADVERSE REACTIONS

6.1 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%).

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

INFECTIONS AND INFESTATIONS: sepsis/septic shock

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

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, 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, pruritus generalized, rash, urticaria

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

Table 2: Adverse Reactions Occurring in ≥3% of Patients Treated with AMMONUL
Patients
N=316

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%)

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