Ravicti

HOS-097167 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile Assessment of adverse reactions was based on exposure in 114 UCD patients (65 adults and 49 children between the ages of 2 months and 17 years) with deficiencies in CPS, OTC, ASS, ASL, ARG, or HHH across 4 short term and 3 long term clinical studies, in which 90 patients completed 12 months duration (median exposure = 51 weeks). At the beginning of the treatment, abdominal pain, nausea, diarrhoea, and/or headache may occur; these reactions usually disappear within a few days even if treatment is continued. The most frequently reported adverse reactions (>5%) during glycerol phenylbutyrate treatment were diarrhoea, flatulence, and headache (8.8% each); decreased appetite (7.0%), vomiting (6.1%); and fatigue, nausea and, skin odour abnormal (5.3% each). Additional adverse reactions have been evaluated in a clinical study including 16 UCD patients less than 2 months of age. The median exposure was 10 months (range 2 to 20 months). Tabulated list of adverse reactions The adverse reactions are listed below, by system organ class and by frequency. Frequency is defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Any adverse reaction reported in one patient met the uncommon criteria. Due to the rarity of the UCD population, and the small size of the medicinal product safety population database (N=114), the adverse reaction frequency for rare and very rare is not known. Table 1. List of adverse reactions System organ class Frequency Adverse reaction Infections and infestations Uncommon Gastrointestinal viral infection Endocrine disorders Uncommon Hypothyroidism Metabolism and nutrition Decreased appetite, increased appetite Common disorders 8  Uncommon Hypoalbuminaemia, hypokalaemia Psychiatric disorders Common Food aversion Nervous system disorders Common Dizziness, headache, tremor Uncommon Dysgeusia, letharg

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HOS-097163 · has-contraindication-information · PDF-Seite 5

• Hypersensitivity to the active substance. • Treatment of acute hyperammonaemia.

HOS-097162 · has-indication-information · PDF-Seite 2

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).

HOS-097165 · has-interaction-information · PDF-Seite 7

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).

HOS-097166 · has-pregnancy-information · PDF-Seite 7

Women of childbearing potential/contraception in males and females The use of RAVICTI in women of childbearing potential must be accompanied by the use of effective contraception (see section 4.4). Pregnancy Studies in animals have shown reproductive toxicity (see section 5.3). There are limited data regarding the use of glycerol phenylbutyrate in pregnant women. Glycerol phenylbutyrate should not be used during pregnancy and in women of childbearing potential not using contraception unless the clinical condition of the woman requires treatment with glycerol phenylbutyrate (see section 4.4). 7 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.

HOS-097164 · has-warning-information · PDF-Seite 5

5 Even while on treatment with glycerol phenylbutyrate, acute hyperammonaemia including hyperammonaemic encephalopathy may occur in a proportion of patients. Reduced phenylbutyrate absorption in pancreatic insufficiency or intestinal malabsorption Exocrine pancreatic enzymes hydrolyse glycerol phenylbutyrate in the small intestine, separating the active moiety, phenylbutyrate, from glycerol. This process allows phenylbutyrate to be absorbed into the circulation. Low or absent pancreatic enzymes or intestinal disease resulting in fat malabsorption may result in reduced or absent digestion of glycerol phenylbutyrate and/or absorption of phenylbutyrate and reduced control of plasma ammonia. Ammonia levels should be closely monitored in patients with pancreatic insufficiency or intestinal malabsorption. Neurotoxicity Reversible clinical manifestations suggestive of neurotoxicity (e.g., nausea, vomiting, somnolence) have been reportedly associated with phenylacetate levels ranging from 499-1,285 mcg/ml in cancer patients who received PAA intravenously. Although these have not been seen in clinical trials involving UCD patients, high PAA levels should be suspected in patients (particularly in children <2months) with unexplained somnolence, confusion, nausea and lethargy who have normal or low ammonia. If symptoms of vomiting, nausea, headache, somnolence, confusion, or sleepiness are present in the absence of high ammonia or other intercurrent illnesses, measure plasma PAA and plasma PAA to PAGN, it should be considered to reduce the glycerol phenylbutyrate dose or increase the frequency of dosing if the PAA level exceeds 500 mcg/ml and the plasma PAA to PAGN ratio exceeds 2.5. Monitoring and laboratory tests The daily dose should be individually adjusted according to the patient’s estimated urea synthetic capacity, if any, amino acid profile, protein tolerance and the daily dietary protein intake needed to promote growth and development. Supplemental amino acid formulations may be necessary to maintain essential amino acids and branched chain amino acids within normal range. Further adjustment may be based on monitoring of plasma ammonia, glutamine, U-PAGN and/or plasma PAA and PAGN as well as the ratio of plasma PAA to PAGN (see section 4.2). Potential for other medicinal products to affect ammonia Corticosteroids Use of corticosteroids may cause the breakdown of body protein and increase plasma ammonia levels. Monitor ammonia levels closely when cor

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