RAVICTI 1.1g / ml oral liquid medication leaflet

RAVICTI 1.1 g/ml oral liquid

Each ml of liquid contains 1.1 g of glycerol phenylbutyrate. This corresponds to a density of 1.1 g/ml.

Oral liquid.

Clear, colourless to pale yellow liquid.

RAVICTI is indicated for use as adjunctive therapy for chronic management of patients with ureacycle disorders (UCDs) including deficiencies of carbamoyl phosphate synthetase I (CPS), ornithinecarbamoyltransferase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL),arginase I (ARG) and ornithine translocase deficiency hyperornithinaemia-hyperammonaemiahomocitrullinuria syndrome (HHH) who cannot be managed by dietary protein restriction and/oramino 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).

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

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 dailydietary protein intake needed to promote growth and development.

The daily dose should be individually adjusted according to the patient’s protein tolerance and thedaily 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 fromsodium phenylbutyrate or from sodium phenylacetate/sodium benzoate injection to RAVICTI aredifferent.

The recommended total daily dose of RAVICTI is based on body surface area and ranges from4.5 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 thefollowing:

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 lessthan 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 thatcontains 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 benzoateto 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 to24 hours for patients stabilised with no further hyperammonaemia is as follows:

* Step 1: 100% dose sodium phenylacetate/sodium benzoate and 50% dose of RAVICTI for4-8 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 continuedaccording to feeding schedule for 4-8 hours.

For data regarding pharmacodynamic and pharmacokinetic properties in this age group, see sections5.1 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 syntheticcapacity, if any, protein tolerance and the daily dietary protein intake needed to promote growth anddevelopment. Dietary protein is approximately 16% nitrogen by weight. Given that approximately47% of dietary nitrogen is excreted as waste and approximately 70% of an administered4-phenylbutyric acid (PBA) dose will be converted to urinary phenylacetylglutamine (U-PAGN), aninitial estimated glycerol phenylbutyrate dose for a 24-hour period is 0.6 ml glycerol phenylbutyrateper gram of dietary protein ingested per 24 hour period assuming all the waste nitrogen is covered byglycerol 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 levelthat is less than half the upper limit of normal (ULN) in patients 6 years and older. In infants andyoung children (generally below 6 years of age) where obtaining fasting ammonia is problematic dueto 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 andassess compliance. Each gram of U-PAGN excreted over 24 hours covers waste nitrogen generatedfrom 1.4 grams of dietary protein. If U-PAGN excretion is insufficient to cover daily dietary proteinintake and the fasting ammonia is greater than half the recommended ULN, the glycerolphenylbutyrate dose should be adjusted upward. The amount of dose adjustment should factor in theamount of dietary protein that has not been covered, as indicated by the 24-h U-PAGN level and theestimated glycerol phenylbutyrate dose needed per gram of dietary protein ingested.

Spot U-PAGN concentrations below the following levels may indicate improper medicinal productadministration 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 productand/or effectiveness of medicinal product administration (e.g., via feeding tube) and considerincreasing 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 whenfasted).

Adjustment based on plasma phenylacetate and phenylacetylglutamine

Symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness in the absence of highammonia 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 guidedosing. The plasma PAA to PAGN (both measured in mcg/ml) ratio has been observed to be generallyless than 1 in patients without PAA accumulation. In patients with a PAA to PAGN ratio exceeding2.5, a further increase in glycerol phenylbutyrate dose may not increase PAGN formation, even ifplasma 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.

Posology is the same for adult and paediatric patients.

Any missed dose should be taken as soon as recognised. However, if the next scheduled dose is within2 hours for adults and within 30 minutes for children, the missed dose should be omitted and the usualdosing schedule resumed. The dose should not be doubled to make up for a missed dose.

Elderly (65 years or older)

Clinical studies of RAVICTI did not include sufficient numbers of subjects ≥ 65 years of age todetermine whether they respond differently than younger subjects. In general, dose selection for anelderly patient should be cautious, usually starting at the low end of the dosing range, reflecting thegreater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or othermedicinal product therapy.

Because conversion of PAA to PAGN occurs in the liver, patients with severe hepatic impairment mayhave 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 impairmentshould be started at the lower end of the recommended dosing range (4.5 ml/m2/day) and kept at thelowest dose necessary to control the patient’s ammonia levels. A plasma PAA to PAGN ratioexceeding 2.5 may indicate saturation of PAA to PAGN conversion capacity and the need for reduceddosing and/or increased frequency of dosing. The plasma PAA to PAGN ratio may be useful in dosemonitoring (see section 5.2).

No studies were conducted in UCD patients with renal impairment; the safety of glycerolphenylbutyrate in patients with renal impairment is unknown. RAVICTI should be used with cautionin patients with severe renal impairment. Preferably such patients should be started and maintained atthe lowest dose necessary to control the blood ammonia levels.

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 glycerolphenylbutyrate is heavier than water and this may result in incomplete administration. Compatibilitystudies have been conducted (see section 4.5). RAVICTI may be added to a small amount of applesauce, 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, orup to 24 hours, refrigerated.

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

The RAVICTI bottle should be opened by pushing down on the cap and twisting to the left. The tip ofthe oral syringe should be placed into the syringe insert and the bottle should be turned upside downwith the syringe still inserted. The oral syringe should then be filled by pulling the plunger back untilthe syringe is filled with the prescribed amount of medicinal product. The oral syringe should betapped to remove air bubbles, while making sure it is filled with the correct amount of liquid. Theliquid can be swallowed from the oral syringe or the oral syringe can be attached to a gastrostomy ornasogastric tube. The same oral syringe should be used for all doses taken each day. It is important toensure that the oral syringe is kept clean and dry between the dosing intervals. The oral syringe shouldnot 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 ofthe day.

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

For additional information regarding method of administration and compatibility/in-use stabilitystudies 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 orgastrostomy 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, eventhose with a nasogastric and/or gastrostomy tube. However, for patients who cannot swallow liquids, anasogastric 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 beallowed to drain after administration

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

* Hypersensitivity to the active substance.

* Treatment of acute hyperammonaemia.

Even while on treatment with glycerol phenylbutyrate, acute hyperammonaemia includinghyperammonaemic 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 theactive moiety, phenylbutyrate, from glycerol. This process allows phenylbutyrate to be absorbed intothe circulation. Low or absent pancreatic enzymes or intestinal disease resulting in fat malabsorptionmay result in reduced or absent digestion of glycerol phenylbutyrate and/or absorption ofphenylbutyrate and reduced control of plasma ammonia. Ammonia levels should be closely monitoredin 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 cancerpatients who received PAA intravenously. Although these have not been seen in clinical trialsinvolving 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 lowammonia.

If symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in theabsence 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 ofdosing 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 syntheticcapacity, if any, amino acid profile, protein tolerance and the daily dietary protein intake needed topromote growth and development. Supplemental amino acid formulations may be necessary tomaintain essential amino acids and branched chain amino acids within normal range. Furtheradjustment may be based on monitoring of plasma ammonia, glutamine, U-PAGN and/or plasma PAAand PAGN as well as the ratio of plasma PAA to PAGN (see section 4.2).

Potential for other medicinal products to affect ammonia

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 usedconcomitantly.

Valproic acid and haloperidol

Hyperammonemia may be induced by haloperidol and by valproic acid. Monitor ammonia levelsclosely 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.

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).

RAVICTI should not be used during pregnancy and in women of childbearing potential not usingcontraception unless the clinical condition of the woman requires treatment with glycerolphenylbutyrate, see section 4.6.

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

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

Glycerol phenylbutyrate and/or its metabolites, PAA and PBA, have been shown to be weak inducersof CYP3A4 enzyme in vivo. In vivo exposure to glycerol phenylbutyrate has resulted in decreasedsystemic exposure to midazolam of approximately 32% and increased exposure to the 1-hydroxymetabolite 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 andthose products predominantly metabolised by the CYP3A4 pathway is possible. Therefore, therapeuticeffects and/or metabolite levels of medicinal products, including some oral contraceptives that aresubstrates 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 havethe potential to affect ammonia levels, see section 4.4.

The effects of glycerol phenylbutyrate on cytochrome P450 (CYP) 2C9 isoenzyme and potential forinteraction 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 andcannot be excluded.

Compatibility studies have demonstrated glycerol phenylbutyrate chemical and physical in-usestability with the following foods and nutritional supplements: apple sauce, ketchup, squash puree, andfive medical formulas (Cyclinex-1, Cyclinex-2, UCD-1, UCD-2, Polycose, Pro Phree and Citrulline)typically consumed by UCD patients (see section 4.2).

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 effectivecontraception (see section 4.4).

Studies in animals have shown reproductive toxicity (see section 5.3). There are limited data regardingthe use of glycerol phenylbutyrate in pregnant women.

Glycerol phenylbutyrate should not be used during pregnancy and in women of childbearing potentialnot using contraception unless the clinical condition of the woman requires treatment with glycerolphenylbutyrate (see section 4.4).

It is unknown whether glycerol phenylbutyrate or its metabolites are excreted in human milk. A risk tothe 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 benefitof 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 (seesection 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 withglycerol phenylbutyrate may cause dizziness or headaches (see section 4.8). Patients should not driveor use machines whilst experiencing these adverse reactions.

Assessment of adverse reactions was based on exposure in 114 UCD patients (65 adults and 49children 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 completed12 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 frequentlyreported 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, skinodour abnormal (5.3% each).

Additional adverse reactions have been evaluated in a clinical study including 16 UCD patients lessthan 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 definedas 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 availabledata). Within each frequency grouping, adverse reactions are presented in order of decreasingseriousness.

Any adverse reaction reported in one patient met the uncommon criteria. Due to the rarity of the UCDpopulation, and the small size of the medicinal product safety population database (N=114), theadverse 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 nutritiondisorders 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 Uncommon Dysphonia, epistaxis, nasal congestion,mediastinal disorder oropharyngeal pain, throat irritation

Gastrointestinal disorders Common Flatulence, diarrhoea, vomiting, nausea,abdominal pain, dyspepsia, abdominaldistension, constipation, oral discomfort,retching

Uncommon Abdominal discomfort, abnormal faeces,dry mouth, eructation, defaecationurgency, upper abdominal pain and/orlower abdominal pain, painfuldefaecation, steatorrhoea, stomatitis

Hepatobiliary disorders Uncommon Gallbladder pain

Skin and subcutaneous tissue Common Abnormal skin odour, acnedisorders Uncommon Alopecia, hyperhidrosis, pruritic rash

Musculoskeletal and Back pain, joint swelling, muscle spasm,connective tissue disorders Uncommon pain in extremity, plantar fasciitis

Renal and urinary disorders Uncommon Bladder pain

Reproductive system and breast Common Metrorrhagiadisorders Uncommon Amenorrhoea, irregular menstruation

General disorders and Common Fatigue, oedema peripheraladministration site conditions Uncommon Hunger, pyrexia

Investigations Common Increased aspartate aminotransferase,alanine aminotransferase increased,increased anion gap, decreasedlymphocyte count, decreased vitamin D

Uncommon Blood potassium increased, bloodtriglycerides increased, electrocardiogramabnormal, low density lipoproteinincreased, prothrombin time prolonged,white blood cell count increased, weightincreased, weight decreased

Adverse reactions reported in more paediatric than adult patients during long-term treatment withglycerol phenylbutyrate included upper abdominal pain (3 of 49 paediatric [6.1%] versus 1 of 51adults [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 RAVICTIhas been evaluated in 16 UCD patients less than 2 months of age and 10 paediatric patients with UCDsaged 2 months to less than 2 years. The median exposure was 10 months (range 2 to 20 months) andmedian 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 Total

Preferred Term (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 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. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tractand metabolism products, ATC code: A16AX09

Glycerol phenylbutyrate is a nitrogen-binding medicinal product. It is a triglyceride containing3 molecules of PBA linked to a glycerol backbone.

UCDs are inherited deficiencies of enzymes or transporters necessary for the synthesis of urea fromammonia (NH +3, NH4 ). Absence of these enzymes or transporters results in the accumulation of toxiclevels of ammonia in the blood and brain of affected patients. Glycerol phenylbutyrate is hydrolysedby pancreatic lipases to yield, PBA, which is converted by beta oxidation to PAA, the active moiety ofglycerol phenylbutyrate. PAA conjugates with glutamine (which contains 2 molecules of nitrogen) viaacetylation in the liver and kidneys to form PAGN, which is excreted by the kidneys. On a molarbasis, PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for wastenitrogen excretion.

Pharmacological effects

In the pooled analysis of studies where patients switched from sodium phenylbutyrate to glycerolphenylbutyrate, ammonia AUC0-24h was 774.11 and 991.19 [(micromol/L)*hour] during treatment withglycerol phenylbutyrate and sodium phenylbutyrate, respectively (n = 80, ratio of geometric means0.84; 95% confidence intervals 0.740, 0.949).

The effect of multiple doses of glycerol phenylbutyrate 13.2 g/day and 19.8 g/day (approximately 69%and 104% of the maximum recommended daily dose) on QTc interval was evaluated in a randomised,placebo- and active-controlled (moxifloxacin 400 mg), four-treatment-arm, crossover study in 57healthy subjects. The upper bound of the one-sided 95% CI for the largest placebo-adjusted, baseline-corrected QTc, based on individual correction method (QTcI) for glycerol phenylbutyrate, was below10 ms, demonstrating that glycerol phenylbutyrate had no QT/QTc prolonging effect. Assay sensitivitywas confirmed by significant QTc prolongation of the positive control, moxifloxacin.

Clinical studies in adult patients with UCDs

Active-controlled, 4-week, noninferiority, blinded crossover study (Study 1)

A randomised, double-blind, active-controlled, crossover, noninferiority study (Study 1) comparedequivalent doses of glycerol phenylbutyrate to sodium phenylbutyrate by evaluating 24-hour venousammonia levels in patients with UCDs who had been on sodium phenylbutyrate prior to enrolment forcontrol of their UCD. Patients were required to have a diagnosis of UCD involving deficiencies of

CPS, OTC, or ASS, confirmed via enzymatic, biochemical, or genetic testing. Patients had to have noclinical evidence of hyperammonaemia at enrolment and were not allowed to receive medicinalproducts known to increase ammonia levels (e.g., valproate), increase protein catabolism (e.g.,corticosteroids), or significantly affect renal clearance (e.g., probenecid).

Glycerol phenylbutyrate was non-inferior to sodium phenylbutyrate with respect to the 24-hour AUCfor ammonia. Forty-four patients were evaluated in this analysis. Mean 24-hour AUCs for venousammonia during steady-state dosing were 866 micromol/L*hour and 977 micromol/L*hour withglycerol phenylbutyrate and sodium phenylbutyrate, respectively (n = 44, ratio of geometric means0.91; 95% confidence intervals 0.799, 1.034).

Consistent with plasma ammonia, blood glutamine levels were lower during glycerol phenylbutyratetreatment as compared with sodium phenylbutyrate in each arm of the crossover study (decrease of44.3 ± 154.43 micromol/L after glycerol phenylbutyrate compared with NaPBA; p = 0.064, pairedt-test; p = 0.048, Wilcoxon signed-rank test).

Open-label uncontrolled extension study in adults

A long-term (12-month), uncontrolled, open-label study (Study 2) was conducted to assess monthlyammonia control and hyperammonaemic crisis over a 12-month period. A total of 51 adult patientsinvolving deficiencies of CPS, OTC, ASS, ASL, ARG, and HHH were enrolled in the study and allbut 6 had been converted from sodium phenylbutyrate to equivalent doses of glycerol phenylbutyrate.

Venous ammonia levels were monitored monthly. Mean fasting venous ammonia values in adults in

Study 2 were within normal limits during long-term treatment with glycerol phenylbutyrate (range:6-30 micromol/L). Of 51 adult patients participating in Study 2, 7 patients (14%) reported a total of 10hyperammonaemic crises during treatment with glycerol phenylbutyrate as compared with 9 patients(18 %) who had reported a total of 15 crises in the 12 months prior to study entry while they werebeing treated with sodium phenylbutyrate.

Clinical studies in paediatric patients with UCDs

The efficacy of glycerol phenylbutyrate in paediatric patients 2 months to 17 years of age involvingdeficiencies of OTC, ASS, ASL, and ARG was evaluated in 2 fixed sequence, open-label, sodiumphenylbutyrate to equivalent dosing of glycerol phenylbutyrate switchover studies (Studies 3 and 4).

Study 3 was 14 days in duration and Study 4 was 10 days in duration.

Glycerol phenylbutyrate was found to be non-inferior to sodium phenylbutyrate with respect toammonia control in both of these paediatric studies. In the pooled analysis of the short-term studies inchildren (Study 3 and Study 4), plasma ammonia was significantly lower after switching to glycerolphenylbutyrate; ammonia AUC0-24h was 626.79 and 871.72 (micromol/L)*hour during treatment withglycerol phenylbutyrate and sodium phenylbutyrate, respectively (n = 26, ratio of geometric means0.79; 95% confidence intervals 0.647, 0.955).

Mean blood glutamine levels were also non-significantly lower after glycerol phenylbutyrate treatmentcompared with sodium phenylbutyrate treatment by -45.2 ± 142.94 micromol/L (p = 0.135, pairedt-test; p = 0.114, Wilcoxon signed-rank test).

Open-label, uncontrolled, extension studies in paediatric patients

Long-term (12-month), uncontrolled, open-label studies were conducted to assess monthly ammoniacontrol and hyperammonaemic crisis over a 12-month period in three studies (Study 2, which alsoenrolled adults, and extensions of Studies 3 and 4). A total of 49 children ages 2 months to 17 yearswith deficiencies of OTC, ASS, ASL, and ARG were enrolled, and all but 1 had been converted fromsodium phenylbutyrate to glycerol phenylbutyrate. Mean fasting venous ammonia values were withinnormal limits during long-term treatment with glycerol phenylbutyrate (range: 17-25 micromol/L). Ofthe 49 paediatric patients who participated in these extension studies, 12 patients (25 %) reported atotal of 17 hyperammonaemic crises during treatment with glycerol phenylbutyrate as compared with38 crises in 21 patients (43 %) in the preceding 12 months prior to study entry, while they were beingtreated with sodium phenylbutyrate.

An open-label, long-term study (Study 5) was conducted to assess ammonia control in paediatricpatients with UCD. The study enrolled a total of 45 paediatric patients between the ages of 1 and17 years with UCD who had completed Study 2 and the safety extensions of Studies 3 and 4. Thelength of study participation ranged from 0.2 to 5.9 years. Venous ammonia levels were monitored at aminimum of every 6 months. Mean venous ammonia values in paediatric patients in Study 5 werewithin normal limits during long-term (24 months) treatment with glycerol phenylbutyrate (range:15-25 micromol/L). Of the 45 paediatric patients participating in the open-label treatment withglycerol phenylbutyrate, 11 patients (24%) reported a total of 22 hyperammonemic crises.

In an additional long term (24 month), uncontrolled, open-label clinical study the safety of RAVICTIhas been evaluated in 16 UCD patients less than 2 months of age and 10 paediatric patients with UCDsaged 2 months to less than 2 years.

Study in children less than 2 months of age

A total of 16 paediatric patients with UCDs aged less than 2 months participated in a long-term(24 months), uncontrolled, open-label study, of which 10 patients converted from sodiumphenylbutyrate to RAVICTI. Three patients were treatment naïve and three additional patients weregradually discontinued from intravenous sodium benzoate and sodium phenylacetate while RAVICTIwas initiated. All patients successfully transitioned to RAVICTI within 3 days, where successfultransition was defined as no signs and symptoms of hyperammonemia and a venous ammonia valueless than 100 micromol/L. The mean normalized venous ammonia values in paediatric patients agedless than 2 months were within normal limits during long-term treatment with glycerol phenylbutyrate(range: 35 to 94 micromol/L).

Hyperammonaemia was reported in 5 (50%) subjects age < 1 month (all serious but non-fatal) and 1subject (16.7%) age 1-2 months (non-serious), which is consistent with more severe disease typesdiagnosed in the neonatal period. In 4 of the 5 subjects age < 1 month, possible risk factors includedinfectious precipitants, hyperammonaemic crisis at baseline, and missing dose. No precipitant triggeror missing dose was reported for the other 2 subjects (1 age < 1 month, 1 age 1-2 months). Doseadjustment was made to 3 subjects age < 1 month.

Study in children 2 months to less than 2 years of age

A total of 10 paediatric patients with UCDs aged 2 months to less than 2 years participated in a longterm (24 months) uncontrolled, open label study, of which 6 patients converted from sodiumphenylbutyrate to RAVICTI and 1 patient converted from sodium phenylbutyrate and sodiumbenzoate. Two patients were treatment naïve and one additional patient was gradually discontinuedfrom intravenous sodium benzoate and sodium phenylacetate while RAVICTI was initiated.

Nine patients successfully transitioned to RAVICTI within 4 days, followed by 3 days of observationfor a total of 7 days, where successful transition was defined as no signs and symptoms ofhyperammonemia and a venous ammonia value less than 100 micromol/L. One additional patientdeveloped hyperammonemia on day 3 of dosing and experienced surgical complications (bowelperforation and peritonitis) following jejunal tube placement on day 4. This patient developedhyperammonemic crisis on day 6, and subsequently died of sepsis from peritonitis unrelated tomedicinal product. Although two patients had day 7 ammonia values of 150 micromol/L and111 micromol/L respectively, neither had associated signs and symptoms of hyperammonemia.

Three patients reported a total of 7 hyperammonemic crises defined as having signs and symptomsconsistent with hyperammonemia (such as frequent vomiting, nausea, headache, lethargy, irritability,combativeness, and/or somnolence) associated with high venous ammonia levels and requiringmedical intervention. Hyperammonemic crises were precipitated by vomiting, upper respiratory tractinfection, gastroenteritis, decreased caloric intake or had no identified precipitating event (3 events).

There was one additional patient who had one venous ammonia level that exceeded 100 micromol/Lwhich was not associated with a hyperammonemic crisis.

ADRs are summarised in section 4.8.

Reversal of the pre-existing neurological impairment is unlikely following treatment and neurologicaldeterioration may continue in some patients.

RAVICTI is a pro-drug of PBA. Upon oral ingestion, PBA is released from the glycerol backbone inthe gastrointestinal tract by pancreatic lipases. PBA derived from glycerol phenylbutyrate is furtherconverted by β-oxidation to PAA.

In healthy, fasting adult subjects receiving a single oral dose of 2.9 ml/m2 of glycerol phenylbutyrate,peak plasma levels of PBA, PAA, and PAGN occurred at 2 h, 4 h, and 4 h, respectively. Upon single-dose administration of glycerol phenylbutyrate, plasma concentrations of PBA were quantifiable in 15of 22 participants at the first sample time post dose (0.25 h). Mean maximum concentration (Cmax) for

PBA, PAA, and PAGN was 37.0 micrograms/ml, 14.9 micrograms/ml, and 30.2 micrograms/ml,respectively. In healthy subjects, intact glycerol phenylbutyrate was not detected in plasma.

In healthy subjects, the systemic exposure to PAA, PBA, and PAGN increased in a dose dependentmanner. Following 4 ml of glycerol phenylbutyrate for 3 days (3 times a day [TID]), mean Cmax and

AUC were 66 mcg/ml and 930 mcg*h/ml for PBA and 28 microgram /ml and 942 mcg*h/ml for PAA,respectively. In the same study, following 6 ml of glycerol phenylbutyrate for 3 days (TID), mean Cmaxand AUC were 100 mcg/ml and 1,400 mcg*h/ml for PBA and 65 mcg/ml and 2,064 mcg*h/ml for

PAA, respectively.

In adult UCD patients receiving multiple doses of glycerol phenylbutyrate, maximum plasmaconcentrations at steady state (Cmax, ss) of PBA, PAA, and PAGN occurred at 8 h, 12 h, and 10 h,respectively, after the first dose in the day. Intact glycerol phenylbutyrate was not detectable in plasmain UCD patients.

Population pharmacokinetic modelling and dosing simulations suggest that PBA enters the circulationabout 70-75% more slowly when given orally as glycerol phenylbutyrate as compared with sodiumphenylbutyrate and further indicate that body surface area is the most significant covariate explainingthe variability of PAA clearance.

In vitro, the extent of human plasma protein binding for 14C-labeled metabolites was 80.6% to 98.0%for PBA (over 1-250 microgram/ml), and 37.1% to 65.6% for PAA (over 5-500 microgram/ml). Theprotein binding for PAGN was 7% to 12% and no concentration effects were noted.

Upon oral administration, pancreatic lipases hydrolyse glycerol phenylbutyrate and release PBA. PBAundergoes β-oxidation to PAA, which is conjugated with glutamine in the liver and in the kidneythrough the enzyme phenylacetyl-CoA: Lglutamine- N-acetyltransferase to form PAGN. PAGN issubsequently eliminated in the urine.

Saturation of conjugation of PAA and glutamine to form PAGN was suggested by increases in theratio of plasma PAA to PAGN with increasing dose and with increasing severity of hepaticimpairment.

In healthy subjects, after administration of 4 ml, 6 ml, and 9 ml 3 times daily for 3 days, the ratio ofmean AUC0-23h of PAA to PAGN was 1, 1.25, and 1.6, respectively. In a separate study, in patientswith hepatic impairment (Child-Pugh B and C), the ratios of mean values for PAA to PAGN among allpatients dosed with 6 ml and 9 ml twice daily ranged from 0.96 to 1.28 and for patients dosed with9 ml twice daily ranged from 1.18-3.19.

In in vitro studies, the specific activity of lipases for glycerol phenylbutyrate was seen in the followingdecreasing order: pancreatic triglyceride lipase, carboxyl ester lipase, and pancreatic lipase-relatedprotein 2. Further, glycerol phenylbutyrate was hydrolysed in vitro by esterases in human plasma. Inthese in vitro studies, a complete disappearance of glycerol phenylbutyrate did not produce molarequivalent PBA, suggesting the formation of mono- or bis-ester metabolites. However, the formationof mono- or bis-esters was not studied in humans.

The mean (SD) percentage of administered PBA eliminated as PAGN was approximately 68.9%(17.2) in adults and 66.4% (23.9) in paediatric UCD patients at steady state. PAA and PBArepresented minor urinary metabolites, each accounting for <1% of the administered dose of PBA.

In a study in patients with clinically decompensated cirrhosis and hepatic encephalopathy (Child-Pugh

B and C), mean Cmax of PAA was 144 mcg/ml (range: 14-358 mcg/ml) after daily dosing of 6 ml ofglycerol phenylbutyrate twice daily, while mean Cmax of PAA was 292 mcg/ml (range:57-655 mcg/ml) after daily dosing of 9 ml of glycerol phenylbutyrate twice daily. The ratio of meanvalues for PAA to PAGN among all patients dosed with 6 ml BID ranged from 0.96 to 1.28 and forpatients dosed with 9 ml twice daily ranged from 1.18-3.19. After multiple doses, a PAAconcentration >200 mcg/L was associated with a ratio of plasma PAA to PAGN concentrations higherthan 2.5.

These findings collectively indicate that conversion of PAA to PAGN may be impaired in patientswith severe hepatic impairment and that a plasma PAA to PAGN ratio > 2.5 identifies patients at riskof elevated PAA levels.

The pharmacokinetics of glycerol phenylbutyrate in patients with impaired renal function, includingthose with end-stage renal disease (ESRD) or those on haemodialysis, have not been studied.

In healthy adult volunteers, a gender effect was found for all metabolites, with women generallyhaving higher plasma concentrations of all metabolites than men at a given dose level. In healthyfemale volunteers, mean Cmax for PAA was 51% and 120% higher than in male volunteers afteradministration of 4 ml and 6 ml 3 times daily for 3 days, respectively. The dose normalized mean

AUC0-23h for PAA was 108% higher in females than in males. However, dosing in UCD patients mustbe individualized based on the specific metabolic needs and residual enzyme capacity of the patient,irrespective of gender.

Population pharmacokinetic modelling and dosing simulations suggest body surface area is the mostsignificant covariate explaining the variability of PAA clearance. PAA clearance was 7.1 L/h, 10.9 L/h,16.4 L/h, and 24.4 L/h, respectively, for UCD patients ages ≤ 2, 3 to 5, 6 to 11, and 12 to 17 years. In16 paediatric UCD patients aged less than 2 months, PAA clearance was 3.8 L/h. In 7 paediatric patientsaged 2 months to under 2 years of age who received RAVICTI for up to 12 months, the concentrationsof PAA, PBA, and PAGN did not increase over the treatment period and the overall median PAA, PBA,and PAGN concentrations in these patients were similar to those observed in older paediatric age groups.

The mean peak ratio of PAA to PAGN in UCD patients aged birth to less than 2 months was higher(mean: 1.65; range 0.14 to 7.07) than for UCD patients aged 2 months to less than 2 years (mean 0.59;range 0.17 to 1.21). No PAA toxicity was observed in the subjects age < 2 months.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity and genotoxicity.

In a rat study, glycerol phenylbutyrate caused a statistically significant increase in the incidence ofpancreatic acinar cell adenoma, carcinoma, and combined adenoma or carcinoma in males andfemales, at a dose of 4.7 and 8.4 times the dose in adult patients, (6.87 ml/m2/day based on combined

AUCs for PBA and PAA). The incidence of the following tumours was also increased in female rats:thyroid follicular cell adenoma, carcinoma and combined adenoma or carcinoma, adrenal corticalcombined adenoma or carcinoma, cervical schwannoma, uterine endometrial stromal polyp, andcombined polyp or sarcoma.

Glycerol phenylbutyrate was not tumourigenic at doses up to 1,000 mg/kg/day in a 26 week mousestudy.

Glycerol phenylbutyrate has been tested in a range of in vitro and in vivo genotoxicity studies, andshown no genotoxic activity.

Glycerol phenylbutyrate had no effect on fertility or reproductive function in male and female rats atclinical exposure levels, however at oral doses up to approximately 7 times the dose in adult patients,maternal as well as male toxicity was observed and the number of nonviable embryos was increased.

Development studies

Oral administration of glycerol phenylbutyrate during the period of organogenesis in rats and rabbitshad no effects on embryo-foetal development at 2.7 and 1.9 times the dose in adult patients,respectively. However, maternal toxicity and adverse effects on embryo-foetal development includingreduced foetal weights and cervical ribs were observed in a rat study with a dose approximately 6times the dose in adult patients, based on combined AUCs for PBA and PAA. No developmentalabnormalities were observed in rats through day 92 postpartum following oral administration inpregnant rats, during organogenesis and lactation.

Juvenile animal study

In a juvenile rat study with daily oral dosing performed on postpartum day 2 through mating andpregnancy after maturation, terminal body weight was dose-dependently reduced in males andfemales, by up to 16% and 12% respectively. Fertility (number of pregnant rats) was decreased by upto 25%, at a dose of 2.6 times the dose in adult patients. Embryo toxicity (increased resorptions) andreduced litter size was also observed.

None.

Not applicable.

3 years.

After the first opening of the bottle, the medicinal product must be used within 14 days and the bottleand its contents discarded, even if not empty.

This medicinal product does not require any special storage conditions.

Clear, Type III glass, bottle with a high density polyethylene (HDPE) child-resistant closure withintegrated syringe insert.

Each bottle contains 25 ml of liquid.

Pack size: 1 bottle.

Any unused medicinal product or waste material should be disposed of in accordance with nationalrequirements.

Based on prescribed dosing volume, patients should be advised to obtain CE marked oral syringeswith suitable size for the dose and compatible with the syringe insert in the bottle from the pharmacy.

One oral syringe should be used each day. The oral syringe should not be rinsed between daily dosesas the introduction of water causes glycerol phenylbutyrate to degrade. The oral syringe should bediscarded after the last dose of each day.

Chemical compatibility of glycerol phenylbutyrate with medical grade silicone nasogastric,gastrostomy, and nasojejunal tubes has been demonstrated. In vitro studies evaluating the percentrecovery of total dose delivered with nasogastric or gastrostomy tubes demonstrated the percent ofdose recovered was >99% for doses > 1 ml and 70% for a 0.5 ml dose. Therefore, it is recommendedthat nasogastric, nasojejunal or gastrostomy tubes only be used to administer doses > 1 ml. If there is aneed to administer a dose of 0.5 ml or less with such nasogastric, gastrostomy or nasojejunal tubes,consideration should be given to the low drug recovery in dosing.

Immedica Pharma AB

SE-113 63 Stockholm

Sweden

EU/1/15/1062/001

Date of first authorisation: 27 November 2015

Date of latest renewal: 25/08/2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.