Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Immedica Pharma AB, SE-113 29, Stockholm, Sweden
Even while on treatment with glycerol phenylbutyrate, acute hyperammonaemia including hyperammonaemic encephalopathy may occur in a proportion of patients.
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.
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.
The daily dose should be individually adjusted according to the patient’s estimated urea synthetic capacity, if any, amino acid profile, protein tolerance and the daily dietary protein intake needed to promote growth and development. Supplemental amino acid formulations may be necessary to maintain essential amino acids and branched chain amino acids within normal range. Further adjustment may be based on monitoring of plasma ammonia, glutamine, U-PAGN and/or plasma PAA and PAGN as well as the ratio of plasma PAA to PAGN (see section 4.2).
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.
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.
Probenecid may inhibit the renal excretion of metabolites of glycerol phenylbutyrate including PAGN.
Effective contraceptive measures must be taken by women of child-bearing potential (see section 4.6).
RAVICTI should not be used during pregnancy and in women of childbearing potential not using contraception unless the clinical condition of the woman requires treatment with glycerol phenylbutyrate, see section 4.6.
Glycerol phenylbutyrate given at the maximum recommended dose contains less than 0.5 g of glycerol per dose.
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.
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.
Other medicinal products such as corticosteroids, valproic acid, haloperidol and probenecid may have the potential to affect ammonia levels, see section 4.4.
The effects of glycerol phenylbutyrate on cytochrome P450 (CYP) 2C9 isoenzyme and potential for interaction with celecoxib has been studied in humans with no evidence of an interaction observed.
Effects of glycerol phenylbutyrate on other CYP isoenzymes have not been studied in humans and cannot be excluded.
Compatibility studies have demonstrated glycerol phenylbutyrate chemical and physical in-use stability with the following foods and nutritional supplements: apple sauce, ketchup, squash puree, and five medical formulas (Cyclinex-1, Cyclinex-2, UCD-1, UCD-2, Polycose, Pro Phree and Citrulline) typically consumed by UCD patients (see section 4.2).
The use of RAVICTI in women of childbearing potential must be accompanied by the use of effective contraception (see section 4.4).
Studies in animals have shown reproductive toxicity (see section 5.3). 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.
Glycerol phenylbutyrate had no effect on fertility or reproductive function in male and female rats (see section 5.3). There are no data for human fertility.
RAVICTI may have major influence on the ability to drive and use machines given that treatment with glycerol phenylbutyrate may cause dizziness or headaches (see section 4.8). Patients should not drive or use machines whilst experiencing these side effects.
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).
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.
Uncommon: Gastrointestinal viral infection
Uncommon: Hypothyroidism
Common: Decreased appetite, increased appetite
Uncommon: Hypoalbuminaemia, hypokalaemia
Common: Food aversion
Common: Dizziness, headache, tremor
Uncommon: Dysgeusia, lethargy, paraesthesia, psychomotor hyperactivity, somnolence, speech disorder
Uncommon: Confusional state, depressed mood
Uncommon: Ventricular arrhythmia
Uncommon: Hot flush
Uncommon: Dysphonia, epistaxis, nasal congestion, oropharyngeal pain, throat irritation
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
Uncommon: Gallbladder pain
Common: Abnormal skin odour, acne
Uncommon: Alopecia, hyperhidrosis, pruritic rash
Uncommon: Back pain, joint swelling, muscle spasm, pain in extremity, plantar fasciitis
Uncommon: Bladder pain
Common: Metrorrhagia
Uncommon: Amenorrhoea, irregular menstruation
Common: Fatigue, oedema peripheral
Uncommon: Hunger, Pyrexia
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
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 RAVICTI 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:
| System Organ Class | Total |
|---|---|
| Preferred Term | (N=16) |
| Blood and lymphatic system disorders | 2 (12.5%) |
| Anaemia, Thrombocytosis | 1 (6.3%) each |
| Gastrointestinal disorders | 3 (18.8%) |
| Diarrhoea | 2 (12.5%) |
| Constipation, Flatulence, Gastrooesophageal reflux disease | 1 (6.3%) each |
| Investigations | 4 (25%) |
| Amino acid level decreased | 1 (6.3%) |
| Gamma-glutamyltransferase increased | 1 (6.3%) |
| Hepatic enzyme increased | 1 (6.3%) |
| Transaminases increased | 1 (6.3%) |
| Metabolism and nutrition disorders | 1 (6.3%) |
| Hypophagia | 1 (6.3%) |
| Skin and subcutaneous tissue disorders | 3 (18.8%) |
| Rash | 3 (18.8%) |
ADRs in patients 2 months to less than 2 years of age:
| System Organ Class | Total |
|---|---|
| Preferred Term | (N=10) |
| Gastrointestinal disorders | 2 (20%) |
| Constipation | 1 (10%) |
| Diarrhoea | 1 (10%) |
| Skin and subcutaneous tissue disorders | 2 (20%) |
| Eczema | 1 (10%) |
| Nail ridging | 1 (10%) |
| Rash | 1 (10%) |
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
