4.1. Therapeutic indications

RAVICTI is indicated for use as adjunctive therapy for chronic management of patients with urea cycle disorders (UCDs) including deficiencies of carbamoyl phosphate synthetase I (CPS), ornithine carbamoyltransferase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), arginase I (ARG) and ornithine translocase deficiency hyperornithinaemia-hyperammonaemia homocitrullinuria syndrome (HHH) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone.

RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).

4.2. Posology and method of administration

RAVICTI should be prescribed by a physician experienced in the management of UCDs.

Posology

RAVICTI must be used with dietary protein restriction and sometimes dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements) depending on the daily dietary protein intake needed to promote growth and development.

The daily dose should be individually adjusted according to the patient's protein tolerance and the daily dietary protein intake needed.

RAVICTI therapy may be required life long unless orthotopic liver transplantation is elected.

Adults and children

The recommended dose for patients naïve to phenylbutyric acid and for patients switching from sodium phenylbutyrate or from sodium phenylacetate/sodium benzoate injection to RAVICTI are different.

The recommended total daily dose of RAVICTI is based on body surface area and ranges from 4.5 ml/m2/day to 11.2 ml/m2/day (5.3 g/m2/day to 12.4 g/m2/day) and should take into account the following:

The total daily dose should be divided into equal amounts and given with each meal or feeding (e.g. three times to six times per day). Each dose should be rounded up to the nearest 0.1 ml for patients less than 2 years of age and 0.5 ml for patients 2 years of age and older.

Recommended starting dose in phenylbutyrate-naïve patients

• 8.5 ml/m2/day (9.4 g/m2/day) in patients with a body surface area (BSA) < 1.3 m2

• 7 ml/m2/day (8 g/m2/day) in patients with a BSA ≥ 1.3 m2

Initial dose in patients switching from sodium phenylbutyrate to RAVICTI

Patients switching from sodium phenylbutyrate to RAVICTI should receive the dose of RAVICTI that contains the same amount of phenylbutyric acid. The conversion is as follows:

• Total daily dose of RAVICTI (ml) = total daily dose of sodium phenylbutyrate tablets (g) x 0.86

• Total daily dose of RAVICTI (ml) = total daily dose of sodium phenylbutyrate powder (g) x 0.81

Initial dose in patients switching from sodium phenylacetate/sodium benzoate injection to RAVICTI

Once stable with controlled ammonia, patients switching from sodium phenylacetate/sodium benzoate to RAVICTI should receive a dose of RAVICTI at the higher end of the treatment range (11.2 ml/m2/day) with measurements of plasma ammonia to guide further dosing.

The recommended daily dose schedule of 8.5 ml/m2/day ‑ 11.2 ml/m2/day over a period of up to 24 hours for patients stabilised with no further hyperammonaemia is as follows:

• Step 1: 100% dose sodium phenylacetate/sodium benzoate and 50% dose of RAVICTI for 4‑8 hours;

• Step 2: 50% dose sodium phenylacetate/sodium benzoate and 100% RAVICTI for 4‑8 hours;

• Step 3: sodium phenylacetate/sodium benzoate discontinued and full dose RAVICTI continued according to feeding schedule for 4‑8 hours.

For data regarding pharmacodynamic and pharmacokinetic properties in this age group, see sections 5.1 and 5.2.

Dose adjustment and monitoring in adults and children

The daily dose should be individually adjusted according to the patient's estimated urea synthetic capacity, if any, protein tolerance and the daily dietary protein intake needed to promote growth and development. Dietary protein is approximately 16% nitrogen by weight. Given that approximately 47% of dietary nitrogen is excreted as waste and approximately 70% of an administered 4‑phenylbutyric acid (PBA) dose will be converted to urinary phenylacetylglutamine (U-PAGN), an initial estimated glycerol phenylbutyrate dose for a 24‑hour period is 0.6 ml glycerol phenylbutyrate per gram of dietary protein ingested per 24 hour period assuming all the waste nitrogen is covered by glycerol phenylbutyrate and excreted as phenylacetylglutamine (PAGN).

Adjustment based on plasma ammonia

The dose of glycerol phenylbutyrate should be adjusted to produce a fasting plasma ammonia level that is less than half the upper limit of normal (ULN) in patients 6 years and older. In infants and young children (generally below 6 years of age) where obtaining fasting ammonia is problematic due to frequent feedings, the first ammonia of the morning should be kept below the ULN.

Adjustment based on urinary phenylacetylglutamine

U-PAGN measurements may be used to help guide glycerol phenylbutyrate dose adjustment and assess compliance. Each gram of U-PAGN excreted over 24 hours covers waste nitrogen generated from 1.4 grams of dietary protein. If U-PAGN excretion is insufficient to cover daily dietary protein intake and the fasting ammonia is greater than half the recommended ULN, the glycerol phenylbutyrate dose should be adjusted upward. The amount of dose adjustment should factor in the amount of dietary protein that has not been covered, as indicated by the 24‑h U-PAGN level and the estimated glycerol phenylbutyrate dose needed per gram of dietary protein ingested.Spot U-PAGN concentrations below the following levels may indicate improper medicinal product administration and/or lack of compliance:

• 9,000 microgram (mcg)/ml for patients under 2 years of age

• 7,000 microgram (mcg)/ml for patients ≥2 years of age with a BSA of ≤1.3

• 5,000 microgram (mcg)/ml for patients ≥2 years of age with a BSA of >1.3

If spot U-PAGN concentrations fall below these levels, assess compliance with medicinal product and/or effectiveness of medicinal product administration (e.g., via feeding tube) and consider increasing the glycerol phenylbutyrate dose in compliant patients to achieve optimal ammonia control (within normal limit for patients under 2 years of age and less than half ULN in older patients when fasted).

Adjustment based on plasma phenylacetate and phenylacetylglutamine

Symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness in the absence of high ammonia or intercurrent illness may be signs of phenylacetic acid (PAA) toxicity (see section 4.4, PAA toxicity). Therefore, measurement of plasma PAA and PAGN levels may be useful to guide dosing. The plasma PAA to PAGN (both measured in mcg/ml) ratio has been observed to be generally less than 1 in patients without PAA accumulation. In patients with a PAA to PAGN ratio exceeding 2.5, a further increase in glycerol phenylbutyrate dose may not increase PAGN formation, even if plasma PAA concentrations are increased, due to saturation of the conjugation reaction. In such cases, increasing the dosing frequency may result in a lower plasma PAA level and PAA to PAGN ratio. Ammonia levels must be monitored closely when changing the dose of glycerol phenylbutyrate.

N-acetylglutamate synthase (NAGS) and CITRIN (citrullinaemia type 2) deficiency

The safety and efficacy of RAVICTI for the treatment of patients with N-acetylglutamate synthase (NAGS) and CITRIN (citrullinaemia type 2) deficiency have not been established.

Paediatric population

Posology is the same for adult and paediatric patients.

Missed dose

Any missed dose should be taken as soon as recognised. However, if the next scheduled dose is within 2 hours for adults and within 30 minutes for children, the missed dose should be omitted and the usual dosing schedule resumed. The dose should not be doubled to make up for a missed dose.

Special populations

Elderly (65 years or older)

Clinical studies of RAVICTI did not include sufficient numbers of subjects ≥ 65 years of age to determine whether they respond differently than younger subjects. 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 of concomitant disease or other medicinal product therapy.

Hepatic impairment

Because conversion of PAA to 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, dose 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 dose monitoring (see section 5.2).

Renal impairment

No studies were conducted in UCD patients with renal impairment; the safety of glycerol phenylbutyrate in patients with renal impairment is unknown. RAVICTI 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.

Method of administration

Oral or gastroenteral use.

RAVICTI should be taken with meals and administered directly into the mouth via an oral syringe. The medicinal product should not be added or stirred into a large volume of other liquid, as glycerol phenylbutyrate is heavier than water and this may result in incomplete administration. Compatibility studies have been conducted (see section 4.5). RAVICTI may be added to a small amount of apple sauce, ketchup, or squash puree and should be used within 2 hours when stored at room temperature (25 °C). The medicinal product may be mixed with medical formulas (Cyclinex-1, Cyclinex-2, UCD‑1, UCD-2, Polycose, Pro Phree and Citrulline) and used within 2 hours when stored at 25 °C, or up to 24 hours, refrigerated.

Patients should be advised that CE marked oral syringes compatible with the integrated syringe insert in the bottle, with suitable size for the prescribed dosing volume can be obtained from a pharmacy (see section 6.6).

The RAVICTI bottle should be opened by pushing down on the cap and twisting to the left. The tip of the oral syringe should be placed into the syringe insert and the bottle should be turned upside down with the syringe still inserted. The oral syringe should then be filled by pulling the plunger back until the syringe is filled with the prescribed amount of medicinal product. The oral syringe should be tapped to remove air bubbles, while making sure it is filled with the correct amount of liquid. The liquid can be swallowed from the oral syringe or the oral syringe can be attached to a gastrostomy or nasogastric tube. The same oral syringe should be used for all doses taken each day. It is important to ensure that the oral syringe is kept clean and dry between the dosing intervals. The oral syringe should not be rinsed between daily doses, as the presence of water causes glycerol phenylbutyrate to degrade. The bottle should be closed tightly after use. The oral syringe should be discarded after the last dose of the day.

RAVICTI may also be administered by CE marked medical grade silicone nasogastric or gastrostomy tube for those patients unable to take the medicinal product by mouth.

For additional information regarding method of administration and compatibility/in-use stability studies please refer to section 6.6.

Preparation for nasogastric tube or gastrostomy tube administration

In vitro studies evaluating the percent recovery of total dose delivered with nasogastric, nasojejunal or gastrostomy tubes demonstrated the percent of dose recovered was > 99% for doses ≥ 1 ml and 70% for a 0.5 ml dose. For patients who can swallow liquids take RAVICTI should be taken orally, even those with a nasogastric and/or gastrostomy tube. However, for patients who cannot swallow liquids, a nasogastric tube or gastrostomy tube may be used to administer RAVICTI as follows:

• An oral syringe should be utilised to withdraw the prescribed dose of RAVICTI from the bottle

• The tip of the oral syringe should be placed onto the tip of the gastrostomy/nasogastric tube

• The plunger of the oral syringe should be used to administer RAVICTI into the tube

• 10 ml of water or medical formula should be used to flush the tube once, and the flush should be allowed to drain after administration

It is not recommended to administer a dose of 0.5 ml or less with nasogastric, gastrostomy or nasojejunal tubes, given the low drug recovery in dosing.

4.3. Contraindications

• Hypersensitivity to the active substance.

• Treatment of acute hyperammonaemia.

4.4. Special warnings and precautions for use

Even while on treatment with glycerol phenylbutyrate, acute hyperammonaemia including hyperammonaemic encephalopathy may occur in a proportion of patients.

Reduced phenylbutyrate absorption in pancreatic insufficiency or intestinal malabsorption

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.

Neurotoxicity

Reversible clinical manifestations suggestive of neurotoxicity (e.g., nausea, vomiting, somnolence) have been reportedly associated with phenylacetate levels ranging from 499‑1,285 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 <2months) 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, it should be considered to reduce the glycerol phenylbutyrate dose or increase the frequency of dosing if the PAA level exceeds 500 mcg/ml and the plasma PAA to PAGN ratio exceeds 2.5.

Monitoring and laboratory tests

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).

Potential for other medicinal products to affect ammonia

Corticosteroids

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.

Valproic acid and haloperidol

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

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

Women of childbearing potential/contraception in males and females

Effective contraceptive measures must be taken by women of child-bearing potential (see section 4.6).

Pregnancy

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.

4.5. Interaction with other medicinal products and other forms of interaction

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 co-administration 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).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/contraception in males and females

The use of RAVICTI in women of childbearing potential must be accompanied by the use of effective contraception (see section 4.4).

Pregnancy

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 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 4.4).

Breast-feeding

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 breast-feeding 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.

Fertility

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.

4.7. Effects on ability to drive and use machines

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 adverse reactions.

4.8. Undesirable 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.

Table 1. List of adverse reactions

System organ class

Frequency

Adverse reaction

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 RAVICTI has been evaluated in 16 UCD patients less than 2 months of age and 10 paediatric 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 reactions are summarized below.

Table 2. List of adverse reactions in patients less than 2 months of age

System organ class

Preferred Term

Total

(N=16)

Blood and lymphatic system disorders

2 (12.5%)

Anaemia,

1 (6.3%)

Thrombocytosis

1 (6.3%)

Metabolism and nutrition disorders

1 (6.3%)

Hypophagia

1 (6.3%)

Gastrointestinal disorders

3 (18.8%)

Diarrhoea,

2 (12.5%)

Constipation

1 (6.3%)

Flatulence

1 (6.3%)

Gastrooesophageal reflux disease

1 (6.3%)

Skin and subcutaneous tissue disorders

3(18.8%)

Rash

3(18.8%)

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%)

Table 3. List of adverse reactions in patients 2 months to less than 2 years of age

System Organ Class

Preferred Term

Total

(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 of suspected adverse reactions

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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

PAA, the active metabolite of glycerol phenylbutyrate, is associated with signs and symptoms of neurotoxicity (see section 4.4) and could accumulate in patients who receive an overdose. In case of overdose, the medicinal product should be discontinued and the patient monitored for any signs or symptoms of adverse reactions.