Glycerol phenylbutyrate

Use of corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels. Monitor ammonia levels closely when corticosteroids and glycerol phenylbutyrate are used concomitantly.

A potential effect on CYP2D6 isoenzyme cannot be excluded and caution is advised for patients who receive medicinal products that are CYP2D6 substrates.

Glycerol phenylbutyrate and/or its metabolites, PAA and PBA, have been shown to be weak inducers of CYP3A4 enzyme in vivo. In vivo exposure to glycerol phenylbutyrate has resulted in decreased systemic exposure to midazolam of approximately 32% and increased exposure to the 1-hydroxy metabolite of midazolam, suggesting that steady-state dosing of glycerol phenylbutyrate results in CYP3A4 induction. The potential for interaction of glycerol phenylbutyrate as a CYP3A4 inducer and those products predominantly metabolised by the CYP3A4 pathway is possible. Therefore, therapeutic effects and/or metabolite levels of medicinal products, including some oral contraceptives, that are substrates for this enzyme may be reduced and their full effects cannot be guaranteed, following coadministration with glycerol phenylbutyrate.

Because conversion of phenylacetic acid (PAA) to phenylacetylglutamine (PAGN) occurs in the liver, patients with severe hepatic impairment may have reduced conversion capability and higher plasma PAA and plasma PAA to PAGN ratio. Therefore, dosage for adult and paediatric patients with mild, moderate or severe hepatic impairment should be started at the lower end of the recommended dosing range (4.5 ml/m²/day) and kept at the lowest dose necessary to control the patient’s ammonia levels. A plasma PAA to PAGN ratio exceeding 2.5 may indicate saturation of PAA to PAGN conversion capacity and the need for reduced dosing and/or increased frequency of dosing. The plasma PAA to PAGN ratio may be useful in dosage monitoring.

No studies were conducted in UCD patients with renal impairment; the safety of glycerol phenylbutyrate in patients with renal impairment is unknown. Glycerol phenylbutyrate should be used with caution in patients with severe renal impairment. Preferably such patients should be started and maintained at the lowest dose necessary to control the blood ammonia levels.

Concomitant use of medicinal products known to inhibit lipase should be given with caution as glycerol phenylbutyrate is hydrolysed by digestive lipase into phenylbutyrate acid and glycerol. This may be associated with increased risk of medicinal product interactions with lipase inhibitors and with lipase contained in pancreatic enzyme replacement therapies.

Probenecid may inhibit the renal excretion of metabolites of glycerol phenylbutyrate including PAGN.

Hyperammonemia may be induced by haloperidol and by valproic acid. Monitor ammonia levels closely when use of valproic acid or haloperidol is necessary in UCD patients.

Reversible clinical manifestations suggestive of neurotoxicity (e.g. nausea, vomiting, somnolence) have been reportedly associated with phenylacetate levels ranging from 499-1285 mcg/ml in cancer patients who received PAA intravenously. Although these have not been seen in clinical trials involving UCD patients, high PAA levels should be suspected in patients (particularly in children <2 months) with unexplained somnolence, confusion, nausea and lethargy who have normal or low ammonia.

If symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or other intercurrent illnesses, measure plasma PAA and plasma PAA to PAGN and consider reduction of glycerol phenylbutyrate dosage or increase the frequency of dosing if the PAA level exceeds 500 mcg/L and the plasma PAA to PAGN ratio exceeds 2.5.

Exocrine pancreatic enzymes hydrolyse glycerol phenylbutyrate in the small intestine, separating the active moiety, phenylbutyrate, from glycerol. This process allows phenylbutyrate to be absorbed into the circulation. Low or absent pancreatic enzymes or intestinal disease resulting in fat malabsorption may result in reduced or absent digestion of glycerol phenylbutyrate and/or absorption of phenylbutyrate and reduced control of plasma ammonia. Ammonia levels should be closely monitored in patients with pancreatic insufficiency or intestinal malabsorption.

Studies in animals have shown reproductive toxicity. There are limited data regarding the use of glycerol phenylbutyrate in pregnant women. Glycerol phenylbutyrate is not recommended during pregnancy and in women of childbearing potential not using contraception.

It is unknown whether glycerol phenylbutyrate or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from glycerol phenylbutyrate therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Women of childbearing potential/contraception in males and females

The use of glycerol phenylbutyrate in women of childbearing potential must be accompanied by the use of effective contraception.

Fertility

Glycerol phenylbutyrate had no effect on fertility or reproductive function in male and female rats. There are no data for human fertility.

Glycerol phenylbutyrate may have major influence on the ability to drive and use machines given that treatment with glycerol phenylbutyrate may cause dizziness or headaches. Patients should not drive or use machines whilst experiencing these side effects.

Summary of the safety profile

Assessment of adverse reactions was based on exposure in 114 UCD patients (65 adults and 49 children between the ages of 2 months and 17 years) with deficiencies in CPS, OTC, ASS, ASL, ARG, or HHH across 4 short term and 3 long term clinical studies, in which 90 patients completed 12 months duration (median exposure = 51 weeks).

At the beginning of the treatment, abdominal pain, nausea, diarrhoea, and/or headache may occur; these reactions usually disappear within a few days even if treatment is continued. The most frequently reported adverse reactions (>5%) during glycerol phenylbutyrate treatment were diarrhoea, flatulence, and headache (8.8% each); decreased appetite (7.0%), vomiting (6.1%); and fatigue, nausea and, skin odour abnormal (5.3% each).

Additional adverse reactions have been evaluated in a clinical study including 16 UCD patients less than 2 months of age. The median exposure was 10 months (range 2 to 20 months).

Tabulated list of adverse reactions

The adverse reactions are listed below, by system organ class and by frequency. Frequency is defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Any adverse reaction reported in one patient met the uncommon criteria. Due to the rarity of the UCD population, and the small size of the medicinal product safety population database (N=114), the adverse reaction frequency for rare and very rare is not known.

Infections and infestations

Uncommon: Gastrointestinal viral infection

Endocrine disorders

Uncommon: Hypothyroidism

Metabolism and nutrition disorders

Common: Decreased appetite, increased appetite

Uncommon: Hypoalbuminaemia, hypokalaemia

Psychiatric disorders

Common: Food aversion

Nervous system disorders

Common: Dizziness, headache, tremor

Uncommon: Dysgeusia, lethargy, paraesthesia, psychomotor hyperactivity, somnolence, speech disorder

Uncommon: Confusional state, depressed mood

Cardiac disorders

Uncommon: Ventricular arrhythmia

Vascular disorders

Uncommon: Hot flush

Respiratory, thoracic and mediastinal disorder

Uncommon: Dysphonia, epistaxis, nasal congestion, oropharyngeal pain, throat irritation

Gastrointestinal disorders

Common: Flatulence, diarrhoea, vomiting, nausea, abdominal pain, dyspepsia, abdominal distension, constipation, oral discomfort, retching

Uncommon: Abdominal discomfort, abnormal faeces, dry mouth, eructation, defaecation urgency, upper abdominal pain and/or lower abdominal pain, painful defaecation, steatorrhoea, stomatitis

Hepatobiliary disorders

Uncommon: Gallbladder pain

Skin and subcutaneous tissue disorders

Common: Abnormal skin odour, acne

Uncommon: Alopecia, hyperhidrosis, pruritic rash

Musculoskeletal and connective tissue disorders

Uncommon: Back pain, joint swelling, muscle spasm, pain in extremity, plantar fasciitis

Renal and urinary disorders

Uncommon: Bladder pain

Reproductive system and breast disorders

Common: Metrorrhagia

Uncommon: Amenorrhoea, irregular menstruation

General disorders and administration site conditions

Common: Fatigue, oedema peripheral

Uncommon: Hunger, Pyrexia

Investigations

Common: Increased aspartate aminotransferase, alanine aminotransferase increased, increased anion gap, decreased lymphocyte count, decreased vitamin D

Uncommon: Blood potassium increased, blood triglycerides increased, electrocardiogram abnormal, low density lipoprotein increased, prothrombin time prolonged, white blood cell count increased, weight increased, weight decreased

Paediatric population

Adverse reactions reported in more paediatric than adult patients during long-term treatment with glycerol phenylbutyrate included upper abdominal pain (3 of 49 paediatric [6.1%] versus 1 of 51 adults [2.0%] and increased anion gap (2 of 49 paediatric [4.1%] versus 0 of 51 adults [0%].

In an additional long term (24 month), uncontrolled, open-label clinical study the safety of glycerol phenylbutyrate has been evaluated in 16 UCD patients less than 2 months of age and 10 pediatric patients with UCDs aged 2 months to less than 2 years. The median exposure was 10 months (range 2 to 20 months) and median exposure in the 2 months to less than 2 years of age was 9 months (range 0.2 to 20.3 months).Adverse drug reactions (ADR) are summarized below.

ADRs in patients less than 2 months of age:

ADRs in patients 2 months to less than 2 years of age: