Glycerol phenylbutyrate
Regulatory sources consulted
Approved indications
- Chronic adjunctive therapy for urea-cycle disorders that cannot be managed with protein restriction and/or amino-acid supplementation alone.
Contraindications
Absolute
- Hypersensitivity to the active substance; treatment of acute hyperammonaemia.
Clinical warnings
- Major warning · It is not a treatment for acute hyperammonaemia; acute hyperammonaemia, including hyperammonaemic encephalopathy, can occur even during treatment. — AEMPS CIMA, Ravicti, ficha técnica 1151062001, secciones 4.3 y 4.4
- Major warning · With unexplained somnolence, confusion, nausea or lethargy and normal or low ammonia, measure phenylacetate and the phenylacetate/phenylacetylglutamine ratio; if phenylacetate exceeds 500 micrograms/mL and the ratio is above 2.5, consider reducing the dose or increasing frequency. — AEMPS CIMA, Ravicti, ficha técnica 1151062001, sección 4.4
- Major warning · Closely monitor ammonia in pancreatic insufficiency or intestinal malabsorption because absorption and ammonia control may be reduced. — AEMPS CIMA, Ravicti, ficha técnica 1151062001, sección 4.4
Drug interactions
- ModerateMidazolam and other predominant CYP3A4 substrates
Mechanism: Glycerol phenylbutyrate and/or its metabolites are weak CYP3A4 inducers; they reduced steady-state systemic midazolam exposure by about 32%.
Recommendation: Review efficacy of CYP3A4 substrates, including some oral contraceptives, and consider alternatives or monitoring if their therapeutic effect is reduced.
https://cima.aemps.es/cima/dochtml/ft/1151062001/FT_1151062001.html
- ModerateLipase inhibitors and pancreatic-enzyme replacement treatments
Mechanism: Glycerol phenylbutyrate is hydrolysed by digestive lipases to phenylbutyric acid and glycerol.
Recommendation: Use with caution; monitor ammonia control when digestive hydrolysis may be altered.
https://cima.aemps.es/cima/dochtml/ft/1151062001/FT_1151062001.html
- ModerateCorticosteroids
Mechanism: Corticosteroids may increase body protein breakdown and ammonia concentration.
Recommendation: Closely monitor ammonia concentration during concomitant administration.
https://cima.aemps.es/cima/dochtml/ft/1151062001/FT_1151062001.html
- ModerateValproic acid and haloperidol
Mechanism: Valproic acid and haloperidol may induce hyperammonaemia.
Recommendation: Closely monitor ammonia concentration if their use is necessary in patients with urea-cycle disorders.
https://cima.aemps.es/cima/dochtml/ft/1151062001/FT_1151062001.html
- ModerateProbenecid
Mechanism: Probenecid may inhibit renal excretion of glycerol phenylbutyrate metabolites, including phenylacetylglutamine and phenylacetic acid.
Recommendation: Account for this interaction when interpreting urinary phenylacetylglutamine and adjusting the dose; monitor plasma ammonia closely.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=15c4da9f-f5e0-4628-b55f-3730be3e1c39https://cima.aemps.es/cima/dochtml/ft/1151062001/FT_1151062001.html
Adverse events
Common (≥1%)
Diarrhoea · Flatulence · Headache · Decreased appetite · Vomiting · Fatigue · Nausea
Rare but serious
Hyperammonaemic encephalopathy · Phenylacetate neurotoxicity
Pregnancy and lactation
Do not use during pregnancy or in women who may conceive without effective contraception unless the clinical situation requires treatment. During breastfeeding, decide whether to stop breastfeeding or treatment according to benefits for mother and child.
Recent literature (PubMed)
Hepatic encephalopathy (HE) is one of the reversible complications of chronic liver disease, associated with a higher mortality rate. In current clinical practice, treatment with rifaximin and lactulose/lactitol is the first line of treatment in HE. With the advance in pathophysiology, a new class of ammonia lowering drugs has been revealed to overcome the hurdle and disease burden. The mechanism of the novel agents differs significantly and includes the alteration in intestinal microbiota, intestinal endothelial integrity, oxidative stress, inflammatory markers, and modulation of neurotoxins. Most of the trials have reported promising results in the treatment and prevention of HE with fecal microbiota transplantation, albumin, probiotics, flumazenil, polyethylene glycol, AST-120, glycerol phenylbutyrate, nitazoxanide, branched-chain amino acid, naloxone, and acetyl-l-carnitine. However, their clinical use is limited due to the presence of major drawbacks in their study design, sample size, safety profile, bias, and heterogenicity. This study will discuss the novel therapeutic targets for HE in liver cirrhosis patients with supporting clinical trial data.
Later-onset urea cycle disorders (UCD) are characterized by variable clinical presentation and unpredictable metabolic decompensation. Current management often relies on a reactive approach, with treatment initiated after clinical manifestations. Glycerol phenylbutyrate (GPB) is widely used for ammonia control in UCD. However, its role in later-onset forms remains incompletely defined, particularly regarding timing of initiation. Available evidence suggests that hyperammonemia-related neurological injury may occur even in apparently stable patients, raising concerns about the adequacy of a wait-and-see strategy. This work provides a clinical perspective integrating current evidence together with personal experience to explore the potential role of pre-emptive GPB therapy in later-onset UCD. The limitations of current approaches are discussed, highlighting the discrepancy between apparent biochemical stability and ongoing neurological risk. We suggest that a proactive treatment strategy may reduce the risk of neurological complications in selected patients with later-onset UCD. We propose a shift from reactive to pre-emptive management, positioning GPB as a potential tool in this context.
Hyperammonaemia is a key pathological feature of liver disease and the primary driver of hepatic encephalopathy (HE). However, the relative roles of increased ammonia production and reduced clearance are poorly understood as is the action of ammonia-targeting drugs for HE. We aimed to quantify whole-body ammonia metabolism in healthy persons and patients with cirrhosis and to validate our method by examining the effects of glycerol phenylbutyrate and lactulose + rifaximin treatment. Ten healthy men and ten male patients with cirrhosis were investigated by 90-minute constant ammonia infusion to achieve steady-state plasma ammonia. Whole-body ammonia clearance was calculated as infusion rate divided by steady-state concentration increase and ammonia production was calculated as clearance multiplied by baseline ammonia concentration. Participants were re-investigated after the ammonia-targeting interventions. In healthy persons, ammonia clearance was 3.5 (3.1-3.9) L/min and ammonia production was 49 (35-63) μmol/min. Phenylbutyrate increased clearance by 11% (4-19%, p = 0.009). In patients with cirrhosis, ammonia clearance was 20% lower at 2.7 (2.1-3.3) L/min (p = 0.02) and production was nearly threefold higher at 131 (102-159) μmol/min (p <0.0001). Lactulose + rifaximin reduced production by 20% (2-37%, p = 0.03). The infusion was generally well-tolerated apart from in one hyperammonaemic patient, with cirrhosis and possible bleeding unrelated to the infusion, who developed clinical HE that reverted when infusion was discontinued. Whole-body ammonia clearance and production may be measured separately using the described technique. This technique identified a lower clearance and a higher production of ammonia in patients with cirrhosis, and showed that phenylbutyrate increases clearance, whereas lactulose + rifaximin reduces production. High blood ammonia plays a key role in cirrhosis-related brain dysfunction. However, the relative roles of reduced ammonia clearance