Ammonul

It is very important that your doctor check your or your child's progress closely while you are receiving this medicine to make sure the medicine is working properly. Blood tests may be needed to check for unwanted effects.

This medicine may cause unwanted effects on the nervous system. Check with your doctor right away if you or your child have lightheadedness, muscle tingling or weakness, sleepiness or unusual drowsiness, or tiredness.

Check with your doctor right away if you or your child have more than one of the following symptoms while receiving this medicine: confusion; deep or fast breathing with dizziness; muscle tremors; nausea; numbness of the feet, hands, and around the mouth; rapid, deep breathing; restlessness; stomach cramps; or unusual tiredness or weakness.

• It is used to treat urea cycle problems.

• If you have an allergy to sodium phenylacetate, sodium benzoate, or any other part of Ammonul (sodium phenylacetate and sodium benzoate).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of low potassium levels like muscle pain or weakness, muscle cramps, or a heartbeat that does not feel normal.
• Signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
• Signs of too much acid in the blood (acidosis) like confusion; fast breathing; fast heartbeat; a heartbeat the does not feel normal; very bad stomach pain, upset stomach, or throwing up; feeling very sleepy; shortness of breath; or feeling very tired or weak.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Very bad dizziness or passing out.
• Headache.
• Feeling very sleepy.
• Feeling very tired or weak.
• Feeling confused.
• Seizures.
• Change in taste.
• Change in hearing.
• Memory problems or loss.
• A burning, numbness, or tingling feeling that is not normal.
• This medicine may cause tissue damage if the drug leaks from the vein. Tell your nurse if you have any redness, burning, pain, swelling, blisters, skin sores, or leaking of fluid where the drug is going into your body.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with Ammonul. It is not known whether Ammonul can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Thus, Ammonul should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether sodium phenylacetate, sodium benzoate, or their conjugation products are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ammonul is administered to a nursing woman.

Pediatric Use

Ammonul has been used as a treatment for acute hyperammonemia in pediatric patients including patients in the early neonatal period [see Dosage and Administration (2)].

Geriatric Use

Clinical studies of Ammonul did not include any patients aged 65 and over to determine whether they respond differently from younger patients. Urea cycle disorders are presently diseases of the pediatric and younger adult populations. No pharmacokinetic studies of Ammonul have been performed in geriatric patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy in this patient population.

Gender

Pharmacokinetic parameters of Ammonul were compared in healthy males and females. Bioavailability of both benzoate and phenylacetate was slightly higher in females than in males. However, conclusions cannot be drawn due to the limited number of subjects in this study.

Hepatic Insufficiency

Limited information is available on the metabolism and excretion of sodium phenylacetate and sodium benzoate in patients with impaired hepatic function. However, metabolic conjugation of sodium phenylacetate and sodium benzoate is known to take place in the liver and kidney. Therefore, caution should be used in administering Ammonul to patients with hepatic insufficiency.

Renal Impairment

The drug metabolites of Ammonul (phenylacetylglutamine and hippurate) and subsequently ammonia are primarily excreted by the kidney. Therefore, use caution and closely monitor patients with impaired renal function who receive Ammonul.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For Ammonul, the following should be considered:

Allergies? Tell your doctor if you have ever had any unusual orallergic reaction to sodium benzoate or sodium phenylacetate. Also tell yourhealth care professional if you are allergic to any other substances, suchas foods, preservatives, or dyes.

Pregnancy? Ammonul has not been studied in pregnant women or animals.

Breast-feeding? It is not known whether Ammonul passes into the breast milk. Although most medicines pass into breast milk in small amounts, many of them may be used safely whilebreast-feeding. Mothers who are taking Ammonul and who wish to breast-feedshould discuss this with their doctor.

Children? Ammonul has been tested in children and, ineffective doses, has not been shown to cause different side effects or problemsthan it does in adults.

Older adults? Many medicines have not been studied specificallyin older people. Therefore, it may not be known whether they work exactlythe same way they do in younger adults or if they cause different side effectsor problems in older people. There is no specific information comparing the use of Ammonul in the elderly with use inother age groups.

Other medicines? Although certain medicines should not be usedtogether at all, in other cases two different medicines may be used togethereven if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking Ammonul, it is especially important that your health care professional know if you are taking the following:

• Corticosteroids - May cause breakdown of body protein and increaseammonia levels in your body

• Penicillins - Use with penicillins may keep the Ammonul from working properly

Other medical problems? The presence of other medicalproblems may affect the use of Ammonul.Make sure you tell your doctor if you have any other medical problems, especially:

• Cancer - Use of Ammonul may increase your chance of side effects

• Edema (swelling) or
• Heart disease - Increased retention of water may make these conditionsworse

• Kidney disease or
• Liver disease - May increase the amount of medicine in your body

Applies to sodium benzoate / sodium phenylacetate: intravenous solution

General

-The most frequently reported adverse reactions (incidence 6% or greater) are vomiting, hyperglycemia, hypokalemia, convulsions, and mental impairment.
-Patients 30 days of age or younger had more blood and lymphatic system disorders and vascular disorders (specifically hypotension), while patients older than 30 days had more GI disorders (specifically nausea, vomiting, and diarrhea).[Ref]

Nervous system

Very common (10% or more): Nervous system disorders (22%)
Common (1% to 10%): Convulsions, mental impairment, brain edema, coma
Frequency not reported: Brain death, brain herniation, subdural hematoma, areflexia, ataxia, brain infarction, brain hemorrhage, cerebral atrophy, clonus, depressed level of consciousness, encephalopathy, nerve paralysis, increased intracranial pressure, tremor[Ref]

Metabolic

Very common (10% or more): Metabolism and nutrition disorders (21%)
Common (1% to 10%): Hyperglycemia, hypokalemia, hyperammonemia, metabolic acidosis, hypocalcemia, acidosis
Frequency not reported: Blood carbon dioxide changes, blood glucose changes, increased blood pH, partial pressure of carbon dioxide changes, alkalosis, dehydration, fluid overload/retention, hypoglycemia, hyperkalemia, hypernatremia, alkalosis, tetany[Ref]

Respiratory

Very common (10% or more): Respiratory, thoracic, and mediastinal disorders (15%)
Common (1% to 10%): Respiratory distress
Frequency not reported: Increased respiratory rate, acute respiratory distress syndrome, dyspnea, hypercapnia, hyperventilation, Kussmaul respiration, pneumonia aspiration, pneumothorax, pulmonary hemorrhage, pulmonary edema, respiratory acidosis, respiratory alkalosis, respiratory arrest/failure[Ref]

Other

Very common (10% or more): General disorders and administration-site conditions (14%), infections (12%), investigations (10%)
Common (1% to 10%): Injury, poisoning, and procedural complications; pyrexia; injection-site reaction
Frequency not reported: Asthenia, chest pain, multiorgan failure, edema, sepsis/septic shock, overdose[Ref]

Gastrointestinal

Very common (10% or more): GI disorders (13%)
Common (1% to 10%): Vomiting, diarrhea, nausea
Frequency not reported: Abdominal distension, GI hemorrhage[Ref]

Hematologic

Very common (10% or more): Blood and lymphatic system disorders (11%)
Common (1% to 10%): Anemia, disseminated intravascular coagulation
Frequency not reported: Coagulopathy, pancytopenia, thrombocytopenia[Ref]

Cardiovascular

Common (1% to 10%): Cardiac disorders, vascular disorders, hypotension
Frequency not reported: Atrial rupture, bradycardia, cardiac or cardiopulmonary arrest/failure, cardiogenic shock, cardiomyopathy, pericardial effusion, decreased cardiac output, flushing, hemorrhage, hypertension, phlebothrombosis/thrombosis[Ref]

Dermatologic

Common (1% to 10%): Skin and subcutaneous tissue disorders
Frequency not reported: Alopecia, blister, generalized pruritus, rash, urticaria[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infection
Frequency not reported: Anuria, urinary retention[Ref]

Psychiatric

Common (1% to 10%): Psychiatric disorders, agitation
Frequency not reported: Acute psychosis, aggression, confusional state, hallucinations[Ref]

Renal

Common (1% to 10%): Renal and urinary disorders
Frequency not reported: Renal failure[Ref]

Hepatic

Frequency not reported: Cholestasis, hepatic artery stenosis, hepatic failure, hepatotoxicity, jaundice[Ref]

Ocular

Frequency not reported: Blindness[Ref]

Oncologic

Frequency not reported: Acquired hemangioma[Ref]

Some side effects of Ammonul may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Absorption

Onset

Mean ammonia concentrations decrease significantly within 4 hours in patients responding to therapy.1

Distribution

Extent

Not known whether sodium phenylacetate or sodium benzoate or their conjugated metabolites are distributed into milk.1

Elimination

Metabolism

Sodium phenylacetate is metabolized in the liver and kidneys to phenylacetylglutamine.1

Sodium benzoate is metabolized in the liver and kidneys to hippuric acid.1

Elimination Route

Phenylacetylglutamine and hippuric acid are principally excreted in urine via glomerular filtration and tubular secretion.1

Special Populations

Sodium phenylacetate and sodium benzoate are metabolized in the liver; limited information available in impaired hepatic function.1

Sodium phenylacetate and sodium benzoate are metabolized and excreted by the kidneys; renal clearance of drug metabolites and ammonia is required.1

Storage

Parenteral

25°C (may be exposed to 15–30°C).1 Diluted solutions are stable for up to 24 hours at room temperature and room lighting conditions.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Do not admix with other infusion solutions.1

Do not admix with other drugs.1