Oliver

A. Approved Indications

• Hepatic Encephalopathy (HE):
  Indicated for the treatment of both acute and chronic hepatic encephalopathy, including all grades (I–IV), associated with liver cirrhosis or acute liver failure.
• Hyperammonemia due to Liver Dysfunction:
  Used to reduce elevated ammonia levels in conditions where hepatic detoxification is impaired.

B. Clinically Accepted Off-Label Uses

• Adjunctive therapy in chronic liver disease and cirrhosis:
  Improves liver function by enhancing ammonia clearance.
• Supportive treatment in non-alcoholic steatohepatitis (NASH):
  May assist in metabolic recovery and ammonia detoxification.

Adults:

• Acute Hepatic Encephalopathy (IV):
  20–40 g/day via intravenous infusion, diluted in 500 mL of 0.9% sodium chloride or 5% dextrose, administered over 4–8 hours. In severe cases, up to 80 g/day may be used under strict monitoring.
• Chronic Hepatic Encephalopathy (Oral):
  5–10 g orally, two to three times daily (total: 10–30 g/day), preferably taken before meals.

Pediatrics:

• Safety and efficacy in children have not been well established.
  Use only under specialist supervision. Starting dose: 100–200 mg/kg/day orally, adjusted based on clinical response and ammonia levels.

Elderly:

• No specific dosage adjustments are necessary.
  Monitor renal and hepatic function and adjust dose if needed.

Renal Impairment:

• Use with caution.
  Monitor renal function and reduce dose if nitrogenous waste accumulates.

Hepatic Impairment:

• Suitable for use in hepatic dysfunction; however, in decompensated or comatose patients, IV use is recommended with close inpatient monitoring.

Routes of Administration:

• Oral: Granules or sachets dissolved in water or juice.
• Intravenous: Diluted in infusion fluids and administered via slow IV drip.

Duration of Therapy:

• Acute HE: Until resolution of symptoms and normalization of ammonia levels.
• Chronic HE: May be used as maintenance therapy.

L-Ornithine L-Aspartate (LOLA) acts by lowering elevated ammonia levels in the blood. L-ornithine enhances the activity of urea cycle enzymes, including carbamoyl phosphate synthetase and ornithine transcarbamylase, thereby promoting the conversion of ammonia into urea in hepatocytes. L-aspartate contributes to ammonia detoxification by facilitating the conversion of ammonia to glutamine, primarily in skeletal muscle and brain tissue. The combined effect of both amino acids reduces systemic ammonia levels, alleviates symptoms of hepatic encephalopathy, and supports overall liver detoxification.

• Absorption: Rapidly absorbed after oral administration.
• Distribution: Widely distributed, with primary activity in the liver and skeletal muscle.
• Metabolism: Ornithine is incorporated into the urea cycle; aspartate is utilized in glutamine synthesis.
• Excretion: Metabolic by-products (urea and glutamine) are excreted via the kidneys.
• Bioavailability: High oral bioavailability; IV administration provides immediate systemic availability.
• Half-life: Not clinically significant, as the compound is rapidly metabolized and utilized endogenously.

• Pregnancy:
  There are no adequate and well-controlled studies in pregnant women. Animal studies have shown no adverse effects. Should be used during pregnancy only if clearly necessary and under medical supervision.
• Lactation:
  It is unknown whether L-ornithine L-aspartate is excreted in human breast milk. Use with caution in breastfeeding women, especially with prolonged or high-dose use.
• Note: Use in pregnancy and lactation only under the guidance of a healthcare provider due to limited human safety data.

• Primary Class: Hepatic Detoxifying Agent
• Subclass: Amino Acid Compound
• Pharmacologic Role: Ammonia-lowering agent used in liver-related neurological complications

• Known hypersensitivity to L-ornithine L-aspartate or any of its excipients
• Severe renal insufficiency (due to potential accumulation of nitrogenous metabolites)
• Inborn errors of the urea cycle (e.g., ornithine transcarbamylase deficiency)

• Renal Impairment: Monitor urea and creatinine levels closely. Reduce dose if accumulation occurs.
• Electrolyte Disturbance: Monitor for hypernatremia or fluid overload during IV use.
• Severe Hepatic Coma: Use only under inpatient care with careful neurological and laboratory monitoring.
• Neurological Status: Monitor mental status and signs of worsening encephalopathy during therapy.
• Concurrent CNS Depressants: Use cautiously to avoid compounded sedation.

Common Adverse Effects (by System):

• Gastrointestinal: Nausea, vomiting, abdominal cramps, diarrhea, flatulence
• Central Nervous System: Headache, light-headedness (rare)
• General: Fatigue, malaise

Serious or Rare Adverse Effects:

• Renal: Azotemia, especially in preexisting renal dysfunction
• Hypersensitivity: Rash, itching, or urticaria (very rare)
• Electrolyte Imbalance: Hypernatremia or dehydration (with high-dose IV)

Timing and Dose Dependency:

• Gastrointestinal symptoms are typically dose-related and reversible with dose reduction.
• Serious effects are rare and usually associated with renal impairment or misuse.

• CNS Depressants (e.g., benzodiazepines): Risk of additive sedation or cognitive impairment in hepatic encephalopathy.
• Lactulose: May be co-administered to enhance ammonia-lowering effects; no direct interaction.
• Protein-rich Diets: May elevate ammonia levels, potentially reducing the effectiveness of LOLA.
• CYP450 Enzymes: L-Ornithine L-Aspartate is not metabolized via the cytochrome P450 system; significant drug interactions are unlikely.

• Hepatic Encephalopathy Guidelines (AASLD, EASL):
  L-Ornithine L-Aspartate is recognized as an effective ammonia-lowering agent, particularly in mild to moderate hepatic encephalopathy (Grades I–II). It is typically used alongside lactulose.
• No recent changes in approved indications or official safety warnings by major regulatory agencies (FDA, EMA, WHO) as of the latest guideline updates.
• Ongoing research is exploring its role in minimal hepatic encephalopathy and chronic liver support therapy.

Oral Formulations (Sachets/Granules):

• Store at 20°C to 25°C (68°F to 77°F)
• Protect from moisture and direct light
• Store in original packaging until use
• Dissolve in water or juice immediately before ingestion

Parenteral Formulations (IV Ampoules):

• Store at 2°C to 8°C (36°F to 46°F)
• Do not freeze
• Use immediately after dilution
• Discard any unused portion after opening
• Protect from light and excessive heat