Ravicti

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
  



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RAVICTI 1.1 g/ml oral liquid 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each ml of liquid contains 1.1 g of glycerol phenylbutyrate. This corresponds to a density of 1.1 g/ml. 
 
 
3. PHARMACEUTICAL FORM 
 
Oral liquid. 
Clear, colourless to pale yellow liquid. 
 
 
4. CLINICAL PARTICULARS 
 
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:  



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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. 



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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). 



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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.  
 
The RAVICTI pack contains the medicinal product and a reclosable bottle cap adapter.  
Patients should be advised that CE marked oral syringes compatible with the reclosable bottle cap 
adapter, 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 
reclosable bottle cap should then be twisted onto the bottle. The tip of the oral syringe should be 
placed into the reclosable bottle cap adapter 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. Neither the reclosable bottle cap 
nor the oral syringe should be rinsed between daily doses, as the presence of water causes glycerol 
phenylbutyrate to degrade. The tethered tab on the reclosable bottle adapter should be closed tightly 
after use. The oral syringe should be discarded after the last dose of the day. The reclosable bottle cap 
should be discarded when the bottle is empty or after 14 days following opening even if the bottle is 
not empty. A new reclosable bottle cap should be used for each new bottle that is opened. 
 
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 



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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/L 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. 
 



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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). 
 



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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. 
 
 



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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 

 



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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 the national reporting system 
listed in Appendix V. 
 
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. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tract 
and metabolism products, ATC code: A16AX09 
 
Mechanism of action 
 
Glycerol phenylbutyrate is a nitrogen-binding medicinal product. It is a triglyceride containing 
3 molecules of PBA linked to a glycerol backbone. 
 
UCDs are inherited deficiencies of enzymes or transporters necessary for the synthesis of urea from 
ammonia (NH3, NH4+). Absence of these enzymes or transporters results in the accumulation of toxic 
levels of ammonia in the blood and brain of affected patients. Glycerol phenylbutyrate is hydrolysed 
by pancreatic lipases to yield, PBA, which is converted by beta oxidation to PAA, the active moiety of 
glycerol phenylbutyrate. PAA conjugates with glutamine (which contains 2 molecules of nitrogen) via 
acetylation in the liver and kidneys to form PAGN, which is excreted by the kidneys. On a molar 
basis, PAGN, like urea, contains 2 moles of nitrogen and provides an alternate vehicle for waste 
nitrogen excretion. 
 
Pharmacodynamic effects 
 
Pharmacological effects 
In the pooled analysis of studies where patients switched from sodium phenylbutyrate to glycerol 
phenylbutyrate, ammonia AUC0-24h was 774.11 and 991.19 [(micromol/L)*hour] during treatment with 
glycerol phenylbutyrate and sodium phenylbutyrate, respectively (n = 80, ratio of geometric means 
0.84; 95% confidence intervals 0.740, 0.949). 
 
Cardiac electrophysiology 
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 57 
healthy 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 below 
10 ms, demonstrating that glycerol phenylbutyrate had no QT/QTc prolonging effect. Assay sensitivity 
was confirmed by significant QTc prolongation of the positive control, moxifloxacin. 
 
Clinical efficacy and safety 
 
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) compared 
equivalent doses of glycerol phenylbutyrate to sodium phenylbutyrate by evaluating 24-hour venous 
ammonia levels in patients with UCDs who had been on sodium phenylbutyrate prior to enrolment for 
control 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 no 
clinical evidence of hyperammonaemia at enrolment and were not allowed to receive medicinal 
products 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 AUC 
for ammonia. Forty-four patients were evaluated in this analysis. Mean 24-hour AUCs for venous 
ammonia during steady-state dosing were 866 micromol/L*hour and 977 micromol/L*hour with 



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glycerol phenylbutyrate and sodium phenylbutyrate, respectively (n = 44, ratio of geometric means 
0.91; 95% confidence intervals 0.799, 1.034).  
 
Consistent with plasma ammonia, blood glutamine levels were lower during glycerol phenylbutyrate 
treatment as compared with sodium phenylbutyrate in each arm of the crossover study (decrease of 
44.3 ± 154.43 micromol/L after glycerol phenylbutyrate compared with NaPBA; p = 0.064, paired 
t-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 monthly 
ammonia control and hyperammonaemic crisis over a 12-month period. A total of 51 adult patients 
involving deficiencies of CPS, OTC, ASS, ASL, ARG, and HHH were enrolled in the study and all 
but 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 10 
hyperammonaemic 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 were 
being treated with sodium phenylbutyrate.  
 
Paediatric population 
 
Clinical studies in paediatric patients with UCDs 
The efficacy of glycerol phenylbutyrate in paediatric patients 2 months to 17 years of age involving 
deficiencies of OTC, ASS, ASL, and ARG was evaluated in 2 fixed sequence, open-label, sodium 
phenylbutyrate 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 to 
ammonia control in both of these paediatric studies. In the pooled analysis of the short-term studies in 
children (Study 3 and Study 4), plasma ammonia was significantly lower after switching to glycerol 
phenylbutyrate; ammonia AUC0-24h was 626.79 and 871.72 (micromol/L)*hour during treatment with 
glycerol phenylbutyrate and sodium phenylbutyrate, respectively (n = 26, ratio of geometric means 
0.79; 95% confidence intervals 0.647, 0.955). 
 
Mean blood glutamine levels were also non-significantly lower after glycerol phenylbutyrate treatment 
compared with sodium phenylbutyrate treatment by -45.2 ± 142.94 micromol/L (p = 0.135, paired 
t-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 ammonia 
control and hyperammonaemic crisis over a 12-month period in three studies (Study 2, which also 
enrolled adults, and extensions of Studies 3 and 4). A total of 49 children ages 2 months to 17 years 
with deficiencies of OTC, ASS, ASL, and ARG were enrolled, and all but 1 had been converted from 
sodium phenylbutyrate to glycerol phenylbutyrate. Mean fasting venous ammonia values were within 
normal limits during long-term treatment with glycerol phenylbutyrate (range: 17-25 micromol/L). Of 
the 49 paediatric patients who participated in these extension studies, 12 patients (25 %) reported a 
total of 17 hyperammonaemic crises during treatment with glycerol phenylbutyrate as compared with 
38 crises in 21 patients (43 %) in the preceding 12 months prior to study entry, while they were being 
treated with sodium phenylbutyrate. 
 
An open-label, long-term study (Study 5) was conducted to assess ammonia control in paediatric 
patients with UCD. The study enrolled a total of 45 paediatric patients between the ages of 1 and 
17 years with UCD who had completed Study 2 and the safety extensions of Studies 3 and 4. The 
length of study participation ranged from 0.2 to 5.9 years. Venous ammonia levels were monitored at a 
minimum of every 6 months. Mean venous ammonia values in paediatric patients in Study 5 were 
within normal limits during long-term (24 months) treatment with glycerol phenylbutyrate (range: 



13 

15-25 micromol/L). Of the 45 paediatric patients participating in the open-label treatment with 
glycerol 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 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. 
 
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 sodium 
phenylbutyrate to RAVICTI. Three patients were treatment naïve and three additional patients were 
gradually discontinued from intravenous sodium benzoate and sodium phenylacetate while RAVICTI 
was initiated. All patients successfully transitioned to RAVICTI within 3 days, where successful 
transition was defined as no signs and symptoms of hyperammonemia and a venous ammonia value 
less than 100 micromol/L. The mean normalized venous ammonia values in paediatric patients aged 
less 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 1 
subject (16.7%) age 1-2 months (non-serious), which is consistent with more severe disease types 
diagnosed in the neonatal period. In 4 of the 5 subjects age < 1 month, possible risk factors included 
infectious precipitants, hyperammonaemic crisis at baseline, and missing dose. No precipitant trigger 
or missing dose was reported for the other 2 subjects (1 age < 1 month, 1 age 1-2 months). Dose 
adjustment 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 long 
term (24 months) uncontrolled, open label study, of which 6 patients converted from sodium 
phenylbutyrate to RAVICTI and 1 patient converted from sodium phenylbutyrate and sodium 
benzoate. Two patients were treatment naïve and one additional patient was gradually discontinued 
from intravenous sodium benzoate and sodium phenylacetate while RAVICTI was initiated.  
 
Nine patients successfully transitioned to RAVICTI within 4 days, followed by 3 days of observation 
for a total of 7 days, where successful transition was defined as no signs and symptoms of 
hyperammonemia and a venous ammonia value less than 100 micromol/L. One additional patient 
developed hyperammonemia on day 3 of dosing and experienced surgical complications (bowel 
perforation and peritonitis) following jejunal tube placement on day 4. This patient developed 
hyperammonemic crisis on day 6, and subsequently died of sepsis from peritonitis unrelated to 
medicinal product. Although two patients had day 7 ammonia values of 150 micromol/L and 
111 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 symptoms 
consistent with hyperammonemia (such as frequent vomiting, nausea, headache, lethargy, irritability, 
combativeness, and/or somnolence) associated with high venous ammonia levels and requiring 
medical intervention. Hyperammonemic crises were precipitated by vomiting, upper respiratory tract 
infection, 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/L 
which 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 neurological 
deterioration may continue in some patients. 
 



14 

5.2 Pharmacokinetic properties 
 
Absorption 
 
RAVICTI is a pro-drug of PBA. Upon oral ingestion, PBA is released from the glycerol backbone in 
the gastrointestinal tract by pancreatic lipases. PBA derived from glycerol phenylbutyrate is further 
converted 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 15 
of 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 dependent 
manner. 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 Cmax 
and 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 plasma 
concentrations 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 plasma 
in UCD patients. 
 
Population pharmacokinetic modelling and dosing simulations suggest that PBA enters the circulation 
about 70-75% more slowly when given orally as glycerol phenylbutyrate as compared with sodium 
phenylbutyrate and further indicate that body surface area is the most significant covariate explaining 
the variability of PAA clearance. 
 
Distribution 
 
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). The 
protein binding for PAGN was 7% to 12% and no concentration effects were noted. 
 
Biotransformation  
 
Upon oral administration, pancreatic lipases hydrolyse glycerol phenylbutyrate and release PBA. PBA 
undergoes β-oxidation to PAA, which is conjugated with glutamine in the liver and in the kidney 
through the enzyme phenylacetyl-CoA: Lglutamine- N-acetyltransferase to form PAGN. PAGN is 
subsequently eliminated in the urine. 
 
Saturation of conjugation of PAA and glutamine to form PAGN was suggested by increases in the 
ratio of plasma PAA to PAGN with increasing dose and with increasing severity of hepatic 
impairment. 
 
In healthy subjects, after administration of 4 ml, 6 ml, and 9 ml 3 times daily for 3 days, the ratio of 
mean AUC0-23h of PAA to PAGN was 1, 1.25, and 1.6, respectively. In a separate study, in patients 
with hepatic impairment (Child-Pugh B and C), the ratios of mean values for PAA to PAGN among all 
patients dosed with 6 ml and 9 ml twice daily ranged from 0.96 to 1.28 and for patients dosed with 
9 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 following 
decreasing order: pancreatic triglyceride lipase, carboxyl ester lipase, and pancreatic lipase–related 



15 

protein 2. Further, glycerol phenylbutyrate was hydrolysed in vitro by esterases in human plasma. In 
these in vitro studies, a complete disappearance of glycerol phenylbutyrate did not produce molar 
equivalent PBA, suggesting the formation of mono- or bis-ester metabolites. However, the formation 
of mono- or bis-esters was not studied in humans. 
 
Elimination 
 
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 PBA 
represented minor urinary metabolites, each accounting for <1% of the administered dose of PBA. 
 
Special populations 
 
Hepatic impairment 
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 of 
glycerol 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 mean 
values for PAA to PAGN among all patients dosed with 6 ml BID ranged from 0.96 to 1.28 and for 
patients dosed with 9 ml twice daily ranged from 1.18-3.19. After multiple doses, a PAA 
concentration >200 mcg/L was associated with a ratio of plasma PAA to PAGN concentrations higher 
than 2.5. 
 
These findings collectively indicate that conversion of PAA to PAGN may be impaired in patients 
with severe hepatic impairment and that a plasma PAA to PAGN ratio > 2.5 identifies patients at risk 
of elevated PAA levels. 
 
Renal impairment 
The pharmacokinetics of glycerol phenylbutyrate in patients with impaired renal function, including 
those with end-stage renal disease (ESRD) or those on haemodialysis, have not been studied. 
 
Gender 
In healthy adult volunteers, a gender effect was found for all metabolites, with women generally 
having higher plasma concentrations of all metabolites than men at a given dose level. In healthy 
female volunteers, mean Cmax for PAA was 51% and 120% higher than in male volunteers after 
administration 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 must 
be individualized based on the specific metabolic needs and residual enzyme capacity of the patient, 
irrespective of gender. 
 
Paediatric population 
Population pharmacokinetic modelling and dosing simulations suggest body surface area is the most 
significant 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. In 
16 paediatric UCD patients aged less than 2 months, PAA clearance was 3.8 L/h. In 7 paediatric patients 
aged 2 months to under 2 years of age who received RAVICTI for up to 12 months, the concentrations 
of 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. 
 



16 

5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity and genotoxicity. 
 
Carcinogenesis 
 
In a rat study, glycerol phenylbutyrate caused a statistically significant increase in the incidence of 
pancreatic acinar cell adenoma, carcinoma, and combined adenoma or carcinoma in males and 
females, 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 cortical 
combined adenoma or carcinoma, cervical schwannoma, uterine endometrial stromal polyp, and 
combined polyp or sarcoma. 
 
Glycerol phenylbutyrate was not tumourigenic at doses up to 1,000 mg/kg/day in a 26 week mouse 
study. 
 
Glycerol phenylbutyrate has been tested in a range of in vitro and in vivo genotoxicity studies, and 
shown no genotoxic activity. 
 
Impairment of fertility 
 
Glycerol phenylbutyrate had no effect on fertility or reproductive function in male and female rats at 
clinical 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 rabbits 
had 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 including 
reduced foetal weights and cervical ribs were observed in a rat study with a dose approximately 6 
times the dose in adult patients, based on combined AUCs for PBA and PAA. No developmental 
abnormalities were observed in rats through day 92 postpartum following oral administration in 
pregnant rats, during organogenesis and lactation. 
 
Juvenile animal study 
 
In a juvenile rat study with daily oral dosing performed on postpartum day 2 through mating and 
pregnancy after maturation, terminal body weight was dose-dependently reduced in males and 
females, by up to 16% and 12% respectively. Fertility (number of pregnant rats) was decreased by up 
to 25%, at a dose of 2.6 times the dose in adult patients. Embryo toxicity (increased resorptions) and 
reduced litter size was also observed. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
None. 
 
6.2 Incompatibilities 
 
Not applicable. 
 



17 

6.3 Shelf life 
 
2 years. 
 
After the first opening of the bottle, the medicinal product must be used within 14 days and the bottle 
and its contents discarded, even if not empty.  
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container  
 
Clear, Type III glass, bottle with a high density polyethylene (HDPE) child-resistant closure. 
 
Each bottle contains 25 ml of liquid.  
 
Pack size: 1 bottle and 1 reclosable bottle cap adapter per carton. 
 
6.6 Special precautions for disposal and other handling 
 
Any unused medicinal product or waste material should be disposed of in accordance with national 
requirements. 
 
Based on prescribed dosing volume, patients should be advised to obtain CE marked oral syringes 
with suitable size for the dose and compatible with the reclosable bottle cap adapter from the 
pharmacy.  
 
One oral syringe should be used each day. The reclosable bottle cap adapter and the oral syringe 
should not be rinsed between daily doses as the introduction of water causes glycerol phenylbutyrate 
to degrade. The oral syringe should be discarded after the last dose of each day. The same reclosable 
bottle cap adapter can be used until a bottle is empty. A new reclosable bottle cap adapter should be 
used for each new bottle that is opened. 
 
Chemical compatibility of glycerol phenylbutyrate with medical grade silicone nasogastric, 
gastrostomy, and nasojejunal tubes has been demonstrated.  In vitro studies evaluating the percent 
recovery of total dose delivered with nasogastric or gastrostomy tubes demonstrated the percent of 
dose recovered was >99% for doses > 1 ml and 70% for a 0.5 ml dose. Therefore, it is recommended 
that nasogastric, nasojejunal or gastrostomy tubes only be used to administer doses > 1 ml. If there is a 
need 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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Immedica Pharma AB 
SE-113 29 Stockholm 
Sweden  
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1062/001 
 
 



18 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 27 November 2015 
Date of latest renewal: 25 June 2020 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

 
  

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


19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



20 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 

Name and address of the manufacturer(s) responsible for batch release 
 
AndersonBrecon (UK) Limited 
Units 2-7 
Wye Valley Business Park 
Brecon Road 
Hay-on-Wye 
Hereford 
Herefordshire 
HR3 5PG 
United Kingdom 

 
Millmount Healthcare Ltd (trading as PCI Pharma Services) 
Block 7, City North Business Campus, 
Stamullen, 
Co. Meath, 
K32 YD60, 
Ireland 
 
Unimedic AB 
Storjordenvägen 2 
SE-864 31 Matfors 
Sweden 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 

 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 

• Periodic safety update reports (PSURs) 
 

The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

• Risk management plan (RMP) 
 

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP. 
 



21 

An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.  

 
• Obligation to conduct post-authorisation measures  

 
The MAH shall complete, within the stated timeframe, the below measures: 

 
Description Due date 

  Non-interventional post-authorisation safety study (PASS):  
Multi-centre prospective non-interventional registry in patients with urea cycle 
disorders on treatment with glycerol phenylbutyrate to characterise patients` 
demographics, and to document long-term safety and clinical outcomes  

 
Final study report 
expected end of 
July 2030. 

 
 
 
 
 
  



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELING AND PACKAGE LEAFLET 
 

 
  



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 
 
 
 
 
 
 
 
 
  



24 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RAVICTI 1.1 g/ml oral liquid 
glycerol phenylbutyrate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml contains 1.1 g of glycerol phenylbutyrate.  
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Oral liquid 
1 bottle of 25 ml 
1 reclosable bottle cap adapter 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral or gastroenteral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
Use within 14 days of opening. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 



25 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Immedica Pharma AB 
SE-113 29 Stockholm 
Sweden  
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1062/001  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
RAVICTI  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN 
 
 
  



26 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RAVICTI 1.1 g/ml oral liquid 
glycerol phenylbutyrate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml contains 1.1 g of glycerol phenylbutyrate. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Oral liquid 
25 ml  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral or gastroenteral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
Use within 14 days of opening. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 



27 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Immedica Pharma AB 
SE-113 29 Stockholm 
Sweden  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1062/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
  



28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



29 

Package leaflet: Information for the patient 
 

RAVICTI 1.1 g/ml oral liquid  
glycerol phenylbutyrate 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine, because it contains 
important information for you. 
• Keep this leaflet. You may need to read it again.  
• If you have any further questions, ask your doctor or pharmacist. 
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What RAVICTI is and what it is used for  
2. What you need to know before you take RAVICTI  
3. How to take RAVICTI  
4. Possible side effects  
5. How to store RAVICTI  
6. Contents of the pack and other information 
 
 
1. What RAVICTI is and what it is used for 
 
RAVICTI contains the active substance ‘glycerol phenylbutyrate’ which is used to treat six known 
‘urea cycle disorders’ (UCDs) in adults and children. The UCDs include deficiencies of certain liver 
enzymes such as 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). 
 
RAVICTI must be combined with a diet reduced in protein intake, and in some cases a diet with 
supplements such as essential amino acids (arginine, citrulline, protein-free calorie supplements). 
 
About urea cycle disorders 
• In urea cycle disorders, the body cannot remove the nitrogen from the protein that we eat. 
• Normally, the body turns the extra nitrogen in the protein into a waste compound called 

‘ammonia’. The liver then removes ammonia from the body through a cycle called the ‘urea 
cycle’. 

• In urea cycle disorders, the body is not able to produce enough liver enzymes to remove the 
extra nitrogen. 

• This means that ammonia builds up in the body. If ammonia is not removed from the body, it 
can harm the brain and lead to low levels of consciousness or coma. 

• Urea cycle disorders are rare. 
 
How RAVICTI works 
RAVICTI helps the body to eliminate waste nitrogen. This reduces the amount of ammonia in your 
body.  
 
 



30 

2. What you need to know before you take RAVICTI 
 
Do not take RAVICTI 
• if you are allergic to glycerol phenylbutyrate 
• if you have acute hyperammonaemia (high levels of ammonia in your blood), which requires 

more rapid intervention (see section “Warnings and precautions”) 
 
If you are not sure if the above apply to you, talk to your doctor or pharmacist before taking 
RAVICTI. 
 
Warnings and precautions   
Talk to your doctor or pharmacist before taking RAVICTI: 
• if you have problems with your kidneys or liver - this is because glycerol phenylbutyrate is 

removed from your body through the kidneys and liver 
• if you have problems with your pancreas, stomach or gut (‘intestines’) - these organs are 

responsible for absorption of glycerol phenylbutyrate into the body 
 
If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking 
RAVICTI. 
 
In some cases such as infection or post-surgery, the amount of ammonia may go up despite treatment 
with this medicine and may damage the brain (hyperammonaemic encephalopathy).  
 
In other cases the amount of ammonia in the blood goes up quickly. In this case, glycerol 
phenylbutyrate will not stop the level of ammonia in your blood from becoming seriously high.  
High levels of ammonia leads to feeling sick (nausea), being sick (vomiting) or feeling confused.  
Tell your doctor or go to the hospital straight away if you notice any of these signs. 
 
Laboratory tests will be needed so your doctor can determine and maintain the correct dose for you.  
 
Other medicines and RAVICTI 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
In particular, tell your doctor or pharmacist if you are taking any of the following medicines, which 
may be less effective when used with glycerol phenylbutyrate. If you take these medicines, you may 
need regular blood tests:  
• midazolam and barbiturates - used for sedation, trouble sleeping or epilepsy 
• contraceptives 
 
Also, tell your doctor if you are taking the following medicines as they may increase the amount of 
ammonia in your body or change how glycerol phenylbutyrate works: 
• corticosteroids - used to treat inflamed areas of the body 
• valproate - a medicine for epilepsy  
• haloperidol - used to treat some mental health problems  
• probenecid - to treat high levels of uric acid in the blood which can cause gout 

(‘hyper-uricaemia’)   
• lipase inhibitors (such as orlistat) – used to treat obesity 
• lipase in pancreatic replacement therapies 
 
If any of the above apply to you (or you are not sure), talk to your doctor before taking RAVICTI. 
 
Pregnancy, contraception and breast-feeding  
• If you are pregnant, tell your doctor before you start taking RAVICTI. If you become pregnant 

while taking RAVICTI, talk to your doctor. RAVICTI should not be used during pregnancy, as a 
risk for your unborn baby cannot be excluded.  



31 

• If you are a woman who could become pregnant, you must use an effective method of 
contraception, during treatment with RAVICTI. Talk to your doctor about the best method of 
contraception for you.   

• You should discuss with your physician before you plan to breast-feed while taking RAVICTI.  
A decision should be made whether to breast-feed or stop taking RAVICTI taking into account 
the benefit of the treatment for you and the benefit of breast-feeding for your baby. This is 
because RAVICTI may pass into breast milk and a risk to the newborn/infant cannot be 
excluded.  

 
Driving and using machines  
RAVICTI may have major influence on the ability to drive and use machines. When taking glycerol 
phenylbutyrate you may feel dizzy or have a headache. Do not drive or use machines whilst 
experiencing these side effects. 
 
 
3.  How to take RAVICTI 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
You must follow a special low protein diet during treatment with glycerol phenylbutyrate. 
• This diet will be designed for you by your doctor and dietician.  
• You must follow this diet carefully. 
• You may need to take supplemental amino acid formulations. 
• You will need to have treatment and to follow a diet throughout your life, unless you have a 

successful liver transplantation. 
 
How much to take  
Your doctor will tell you how much RAVICTI you should take each day. 
• Your daily dose will depend on your size and weight, the amount of protein in your diet, and 

your overall urea cycle disorder condition.  
• Your doctor may give you a lower dose if you have kidney or liver problems. 
• You will need regular blood tests so your doctor can determine the correct dose for you. 
• Your doctor might tell you to take RAVICTI more than 3 times each day. In small children, this 

may be 4 to 6 times a day. There must be at least 3 hours between each dose. 
 
Taking this medicine  
Your doctor will tell you how to take RAVICTI oral liquid. It can be taken in the following ways: 
• by mouth  
• through a tube that goes through your tummy (‘abdomen’) to the stomach - called a 

‘gastrostomy tube’  
• through a tube that goes through your nose to the stomach - called a ‘nasogastric tube’   

 
Take RAVICTI by mouth unless otherwise directed by your doctor.  
 
RAVICTI and meals 
Take RAVICTI with or straight after a meal. Young children should be given the medicine during or 
straight after a feeding.   
 
Measuring the dose  
• Use an oral syringe to measure your dose.  
• You should have the medicine with the reclosable bottle cap adapter along with an oral syringe 

to administer the correct amount of glycerol phenylbutyrate. 
 

1. Open the bottle of RAVICTI by pushing down on the cap and twisting to the left. 



32 

2. Twist the reclosable bottle cap adapter onto the bottle. 

3. Place the tip of the oral syringe into the reclosable bottle cap adapter.  

4. Turn the bottle upside down with the oral syringe still inserted. 

5. Fill the oral syringe by pulling the plunger back until the syringe is filled with the amount of 
glycerol phenylbutyrate liquid that your doctor has told you to take. 

− Note: If possible, use the oral syringe ml size that is nearest to (but not smaller than) 
the recommended dose (for example, if the dose is 0.8 ml, use a 1 ml oral syringe). 

 
6. Tap the oral syringe to remove air bubbles, making sure you have filled it with the correct 

amount of liquid.  

  
7. Swallow the liquid from the oral syringe or attach the oral syringe to a gastrostomy or 

nasogastric tube.  

 



33 

8. Important note: Do not add or stir RAVICTI into larger volumes of liquid such as water or 
juice as RAVICTI is heavier than most liquids. Mixing RAVICTI with large volumes of liquid 
may result in you not getting the full dose.  

9. RAVICTI can be added to a small amount of soft foods, such as ketchup, medical formulas, 
apple sauce or squash puree. 

10. If the volume of your oral syringe is smaller than your prescribed dose, you will have to repeat 
these steps to get your full dose. Use one oral syringe for all doses taken each day. 

11. After you take your full dose, have a drink of water to make sure no medicine is left in your 
mouth, or flush the gastrostomy or nasogastric tube with 10 ml of water using a new oral 
syringe. The syringe used to flush the gastrostomy or nasogastric tube shall not be used for 
measuring the dose of RAVICTI to avoid introduction of water into the medicine. 

 
12. Close the tab on the reclosable bottle cap adapter.   

 
13. Important note: Do not rinse the reclosable bottle cap adapter or the oral syringe between 

daily doses as the introduction of water causes glycerol phenylbutyrate to degrade. If 
RAVICTI gets in contact with water, the liquid will become cloudy in appearance. Store bottle 
and oral syringe in a clean, dry place between doses. 

14. Discard the oral syringe after the last dose of the day. Do not re-use the oral syringe for 
measuring the dose of RAVICTI on another day. The reclosable bottle cap adapter can be used 
until the bottle is empty. A new reclosable bottle cap adapter should be used when a new 
bottle is opened.  

15. Remaining unused syringes should be kept for use with another bottle. Each bottle should be 
discarded after 14 days. 

 
If you take more RAVICTI than you should  
If you take more of this medicine than you should, talk to a doctor.  
 
If you notice any of the following signs, talk to a doctor or go to a hospital straight away as these may 
be signs of overdose or high ammonia: 
• feeling sleepy, tired, light-headed or sometimes confused  
• headache  
• changes in taste  
• problems hearing  
• feeling disorientated  
• less able to remember things  
• existing neurological conditions may get worse 
 
If you forget to take RAVICTI 
If you forget a dose, take the missed dose as soon as you remember. However, for adults, if the next 
dose is in less than 2 hours, then skip it and take your next dose as normal. 
For children: if the next dose is in less than 30 minutes, then skip it and give the next dose as normal. 
• Do not take a double dose to make up for a forgotten dose. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 



34 

 
If you stop taking RAVICTI  
You will need to take this medicine and follow a special low protein diet throughout your life. Do not 
stop taking glycerol phenylbutyrate without talking to your doctor.  
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
Tell your doctor or pharmacist if you notice any side effects.  
The following side effects may happen with this medicine: 
 
Common: may affect up to 1 in 10 people  
• stomach bloating or pain, constipation, diarrhoea, heartburn, wind, vomiting, feeling sick 

(nausea), pain in the mouth, retching  
• swelling of the hands or feet, feeling tired  
• feeling dizzy, headache or tremor 
• decreased or increased appetite  
• not wanting to eat some foods 
• bleeding between menstrual periods 
• acne, skin smells abnormal 
• tests show increased liver enzyme levels, imbalance of salts in the blood, low levels of a type of 

white blood cell (‘lymphocytes’) or low levels of vitamin D  
 

Uncommon: may affect up to 1 in 100 people  
• dry mouth, burping, stomach ache or discomfort, changes in your stools such as being oily, 

urgent need for bowel movements, painful bowel movements, inflammation of mouth and lips  
• feeling hungry, increased temperature  
• hot flushes 
• gallbladder pain  
• bladder pain  
• back pain, joint swelling, muscle spasms, pain in the arms or legs, heel spur  
• viral infection in the gut 
• feeling of pins and needles, feeling very restless, sleepiness, feeling drowsy, problems with 

speech, feeling confused, feeling depressed, alteration of taste 
• menstrual periods stop or are irregular  
• voice disorder, nosebleeds, stuffy nose, sore or painful throat 
• hair loss, sweating more than usual, itchy rash,  
• uneven heartbeat 
• reduced thyroid function 
• weight loss or weight gain 
• tests show higher or lower potassium in your blood 
• tests show higher levels of triglycerides, low density lipo-protein or white cells in your blood  
• tests show abnormal ECG (‘electrocardiogram’)  
• tests show prothrombin time is longer 
• tests show low albumin in your blood 

 
Side effects in children less than 2 months of age 
The following side effects have been observed in a clinical study including 16 patients less than 
2 months of age: 
• diarrhoea, constipation, wind, reflux of stomach contents, poor feeding 
• rash 
• reduced number of red blood cells 
• increased number of platelets (may cause blood clot) 
• increased liver enzymes 



35 

• decreased amino acid levels 
 

Side effects in children 2 months to less than 2 years of age 
• diarrhoea, constipation 
• eczema, nail ridging, rash 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store RAVICTI 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use RAVICTI after the expiry date which is stated on the carton and the bottle label after the 
letters “EXP”. The expiry date refers to the last day of that month. 
  
This medicinal product does not require any special storage conditions. Once the bottle is open, you 
must use your medicine within 14 days of opening. The bottle should be discarded even if it is not 
empty. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What RAVICTI contains  
• The active substance is glycerol phenylbutyrate.  
• Each ml of liquid contains 1.1 g of glycerol phenylbutyrate. This corresponds to a density of 

1.1 g/ml. 
• There are no other ingredients.  

 
What RAVICTI looks like and contents of the pack 
The liquid is filled into a 25 ml clear glass bottle and capped with a plastic, child-resistant cap. The 
bottle is packed with a reclosable bottle cap adapter.  
In order to ensure correct dosing of RAVICTI, CE-marked oral syringes with suitable size for the dose 
and compatible with the reclosable bottle cap adapter can be obtained from the pharmacy. Ask your 
doctor or pharmacist which type of syringes you need to obtain based on the prescribed dose volume.  
 
Marketing Authorisation Holder  
Immedica Pharma AB 
SE-113 29 Stockholm 
Sweden  
 
Manufacturer  
AndersonBrecon (UK) Limited 
Units 2-7, 
Wye Valley Business Park, 
Brecon Road, 
Hay-on-Wye, 
Hereford, Herefordshire, HR3 5PG 
United Kingdom 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


36 

Millmount Healthcare Ltd (trading as PCI Pharma Services) 
Block 7, City North Business Campus, 
Stamullen, 
Co. Meath, 
K32 YD60, 
Ireland 
 
Unimedic AB 
Storjordenvägen 2 
SE-864 31 Matfors 
Sweden 
 
 
This leaflet was last revised in  
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments.  
 

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

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	LABELING AND PACKAGE LEAFLET
	A. LABELLING
	B. PACKAGE LEAFLET