Ravicti 1.1 g/ml oral liquid

4.4    Special warnings and precautions for use

Neurotoxicity

[....]

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/mlL and the plasma PAA to PAGN ratio exceeds 2.5.

6.3    Shelf life

32 years.

PIL updated following variation approval - refer to SPC updates

SPC updated following EMEA/H/C/003822/IB/0037/G approval

Only the updated SPC paragraph sections are shown below

4.2       Posology and method of administration

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 integratedreclosable bottle cap adaptersyringe insert in the bottle, with suitable size for the prescribed dosing volume can be obtained from a pharmacy (see section 6.6).

The RAVICTI bottle should be opened by pushing down on the cap and twisting to the left. The reclosable bottle cap should then be twisted onto the bottle. The tip of the oral syringe should be placed into the reclosable bottle capsyringe adapterinsert 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 tThe oral syringe should not be rinsed between daily doses, as the presence of water causes glycerol phenylbutyrate to degrade. The tethered tab on the reclosable The 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

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.

6.5       Nature and contents of container

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

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 syringe insert in the bottlereclosable 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.

10.     DATE OF REVISION OF THE TEXT

25/06/202028/04/2021

SPC updated followijng renewal application

Updated SPC sections are shown below

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

4.2       Posology and method of administration

4.4       Special warnings and precautions for use

4.6       Fertility, pregnancy and lactation

4.7       Effects on ability to drive and use machines

4.8       Undesirable effects

5.1       Pharmacodynamic properties

5.2       Pharmacokinetic properties

5.3       Preclinical safety data

6.5       Nature and contents of container

6.6       Special precautions for disposal and other handling

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10.     DATE OF REVISION OF THE TEXT

25/06/2020